CA1326668C - Ethers and thioethers having therapeutical activity, their preparation and pharmaceutical compositions containing them - Google Patents
Ethers and thioethers having therapeutical activity, their preparation and pharmaceutical compositions containing themInfo
- Publication number
- CA1326668C CA1326668C CA000574445A CA574445A CA1326668C CA 1326668 C CA1326668 C CA 1326668C CA 000574445 A CA000574445 A CA 000574445A CA 574445 A CA574445 A CA 574445A CA 1326668 C CA1326668 C CA 1326668C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- methyl
- group
- phenoxy
- thia
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyridine Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Abstract Compounds of formula I
Description
1 32666~
ETHERS AND THIOETHERS HAVING TH~RAPEUTICAL ACTIVITY, THEIR
PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention concerns compounds endowed with mucolytic and antitussive acti~itiesO
The compounds of the invention have the ~ollowing general formula I
R1______ R2 - (Ar)-O-CHz-(B3-CH2-X-R-T (I) 1 0 h~3 wherein:
Ar is an unsubstituted or polysubstituted phenyl ring;
B is selected in the group cosnisting o~ a valency bond, - (CH20-CHz) n' and 1,3-dioxolan-2,4-diyl or 1,3-thioxolan-2,4-diyl radical group which may be indif~erently bonded to the remaining parts of the molecule by means of C(2) and C(43 carbons of the heterocyclic ring;
X is sulphur or oxygen;
T is a 2-, 3- or 4-p~ridyl, carboxyl, ~CO2R6, -COR6, -CO2NH2, -CONRdRe, -CO-NH-CH(Rc)-CO2Ra or a di-(C1-C4)~alkylamino-(Cl-C4) -alkylaminocarbonyl-, hydroxy, (C1-C4)-alkoxy-(C1-C4)-alkyl-aminocarbonyl-,di-(C1-C4)--alkyl-amino (C1-C4)-alkoxy-(C1-C~)-alkyl-amino-carbonyl or 2 , 3-, 4-pyridylmethylamino-carbonyl group;
p ents (CH~)n , -CH~R4)-, ~CH2-CH(NH23- or -C~I2-CH(NH-CORa3- group;
R1, R2 and R3, that can be the same or diffPrent, are selected from the group consisting of hydrogen, hydroxy, (C1 C5) acyloxy, (C1--C4)--alkyl, (C1--C43--alkox~l, (C2 C~)--alkenyl, halogtan, (C1~C~)-acylamino, phenyl, phenoxy, t, . .~ ' .
'' ~
., .
~ 2 --imidazol-l-yl, carboxyl, (C1-C33-alkoxy-carbonyl, carboxy-(C1-C4)-alkyl;
R4 is a (C1-C4)-alkyl or a (C2-C4)-alkenyl group;
Ra is hydrogen or a (C1-C4)-alkyl group;
R6 is a (C1-C6)-alkyl group optionally substituted by (C1-C6)-alkoxy, carboxyl, ~C1-C4~-alkylamino, di-(C,-C4)-alkylamino, morpholin-N-yl, piperidin-l-yl, 4-~C1-C4)-alkyl-piperazin-l-yl, lC3-C6)-alkenyl, phenyl or phenyl-(C1-C6)-alkyl groups;
Rc is hydrogen or a (C1-C6)-alkyl, or (C6-C14)-ar-(C1-C4)-alkyl, or heteroalkyl group of a residue of a natural ~-aminoacid, and Rd and Re, which can be the same or dif~erent, are hydrogen, a (C1-C6)-alkyl optionally substituted by (C1-C6)-alkoxy, morpholin-N-yl, piperidin-l-yl, 4-(C1-C4)-alkyl-piperazin-l-yl, hydroxy-(C1-C4)-alkoxy-(C1-C4)-alkyl or di-(C1-C4~-alkylamino-(C1-C4)-alkoxy- (C~C4) -alkyl group or Rd and Re together with the nitrogen atom to which they are bonded form a heterocyclic ring selected ~rom the group consisting o~ morpholin-N-yl, piperidin-l-yl and 4-(C1-C4)-alkyl-piperazin-l-yl.
In the scope of the invention are also included pharmaceutically acceptable salts, optical antipodes, i.e.
the single enantiomers, mixtures of optical antipodes, diasteroisomers and mixtures o~ diasteroisomers of I compounds of formiula I.
I ~ The above mentioned carboxy groups are optionally sali~ied ¦: with an ammonium or alkaline cation.
The term halogen i5 to be understood to mean ~luorine, chlorine, bromine and iodine, but preferably bromine and l~ chlorine.
i~ ~ The aralkyl radical can be phenyl-~C~-C4)-alkyl or naphthyl (C1-C4) -alkyl .
1 ~:
1: .-::,.
:1. - ::
A (C1-C6)-alkyl, a (C6-C14~-ar-(C1-C4~-alkyl and a heteroalkyl residue o~ a natural ~-aminoacid means for example N-alanyl, N-valinyl, N-phenylalanyl, N-methionyl or N-histidinyl.
More particularly the present invention concerns addition salts with pharmaceutically acceptable bases, when in the compounds of formula I there is a free carboxylic group and addition salts with pharmaceutically acceptable acids, when in the compounds of formula I there is a basic organic portion.
Typical examples o~ non-toxic and pharmaceutically acceptable bases are organic bases, e.g. amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diisopropylamine, N-methyl-N-hexylamine, tromethamine, cyclohexylamine, N-methyl~N-cyclohexylamine, ~-I phenylethyleamine, B-phenylethylamine, N,N-I dimethylethanolamine, N,N-diethylethanolamine, ! ethylenediamine, piperidine, morpholine, pipera2ine, galactamine, N-methylglucamine, ephedrine, lysine, arginine ~l and inorganic bases such as hydroxides of alkaline and j alkaline-earth metals, as well as zinc and aluminum hydroxides.
Typical examples o~ non-toxic, pharmacologically acceptable acids are organic acids, such a~ acetic, formic, propionic, fumaric, tartaric, maleic, malic, malonic, benzoic, i salicylic, 3,4,5-trimethoxybenzoic, methanesulphonic, benzenesulphonic, camphorsulphonic, lactic, aspartic, glutammic, L- or D-2-phenyl-thiazolidine-5 carboxylic acids, cystine and cysteine; and inorganic acids such as l nitric, phosphoric, sulphuric, hydrochloric and hydrobromic j acids.
, According to the invention, alXyl, alkenyl, alkoxy group~
-, may have linear or branched chain.
,~ . .
.t Non-limitative examples of compounds of the invention are those whexein the group R1 , R~ (Ar) is phenyl, 2-hydroxyphenyl, 2- or 4-methoxyphenyl, 2-methoxy-4-allyl~phenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxy-4 hydroxyphenyl, 3,5-ditert.butoxy-4-hydroxy-phenyl, 4-acetamidophenyl, 4-ethoxycarbonylcarboxyamido-phenyl, 4-(imidazol-1-yl) 2-allyl-phenyl. B is a single bond or a 1,3-dioxolane-4,2-diyl, a 1,3-thioxolane-4,2-diyl, a 1,3-thioxolane-2,4-diyl or a 1,3-dioxolane-2,4-diyl group of the formulae:
o~l and X - R - T are one of the groups having the above reported formulae. . :
:~' ,:
j: : ~ ..
1 3~6668 Particularly preferred examples of compound~ of the ..
invention are: .
- ethyl 4-/4-(2-~etho~yphenoxy)-methyl-(E) (1,3)-dioxolane-2-yl/-3-oxa butanoate;
- 3-oxa-4-/4-(2-methoxyphenoxy)-methyl-(E)-(1,3) dioxolane-2-yl~-butanoic acid;
- 3-oxa-4-/4-(2-methoxyphenoxy9-mcthyl-(Z)-(1,3) dioxolane-2-yl/-butanoic acid; :
- 3-oxa-4-/4-(2-methoxyphenoxy)-methyl-(Z,E) (1,3)-dioxolane-2-yl/-butanoic acid;
- 3-oxa-4-/4-(3,5-diterbutyl-4-hydroxyphenoxy)-methyl (Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
l - 3-oxa-4-/-(3,5-dimethoxy-4~hydroxyphenoxy)methyl I (Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
! _ 3-oxa-4-/4-(3,4,5-trimethoxypheno~y)methyl-(Z,E) :l (193)-dioxolane-2-yl/--butanoic acid; -~
¦ - 3-oxa-4-/4-(2-methoxy-4-allyl-phenoxy~-methyl-(Z,E3-~ (1,3)-dioxolane-2-yl/-butanoic acid; .
- 3-oxa-4-/4-(4-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid; :~
- 3-thia-4-/4-(2 ~ethoxypherloxy~methyl-~Z,E)-dioxolane-2-yl~-butanoic acidl;
- 3-thi,~-4-/4-(2--phenoxy)methyl-(Z)-(1,3)-d;oxolane-2-yl/- butanoic acid; -~
. - 3-thia-4-/4-(4-methoxypheno~y)methyl-(Z,E3-(1,3)-l dioxolane-2-yl~-butanoic acid;
- 3-thia-4-/4-(2-methoxyphenoxy)methyl-(E)-(1,3)~
~ dioxolane-2-yl/-butanoic acid; -~ :
.!i _ 3-thia-4-/4-(~-hydroxyphenoxy)methyl-tZ,E)-(1~3)-¦~ dioxolane-2-yl/-butanoic acid; .
- 3-thia-4-/4-(3,'l,5-trimethoxyphenoxy3methyl-(Z,E)- :: .
3)-dioxolane-2-yl~-butanoic acid;
~:: - 3-thia-4-/'l-(3,5-dimetho~y-4-hydroxy-phenoxy)~ethyl-(Z,E)-~1,3)-dioxolane-2-yl/-butanoic acid;
.
". : , ... .
, - 3-thia-4-/4-(4-imidazol-1-yl-phenoxy)-methyl-(Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(3,5-diterbutyl-4-hydroxy-phenoxy)-methyl (Z,E)-t1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/-4-(4-aceta~idophenoxy~methyl-~Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(2-methoXY-4-allyl-phenoXy~nlethY
(Z,E)-(1,3)-dioxolane-2-yl/butanoic acid;
ETHERS AND THIOETHERS HAVING TH~RAPEUTICAL ACTIVITY, THEIR
PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention concerns compounds endowed with mucolytic and antitussive acti~itiesO
The compounds of the invention have the ~ollowing general formula I
R1______ R2 - (Ar)-O-CHz-(B3-CH2-X-R-T (I) 1 0 h~3 wherein:
Ar is an unsubstituted or polysubstituted phenyl ring;
B is selected in the group cosnisting o~ a valency bond, - (CH20-CHz) n' and 1,3-dioxolan-2,4-diyl or 1,3-thioxolan-2,4-diyl radical group which may be indif~erently bonded to the remaining parts of the molecule by means of C(2) and C(43 carbons of the heterocyclic ring;
X is sulphur or oxygen;
T is a 2-, 3- or 4-p~ridyl, carboxyl, ~CO2R6, -COR6, -CO2NH2, -CONRdRe, -CO-NH-CH(Rc)-CO2Ra or a di-(C1-C4)~alkylamino-(Cl-C4) -alkylaminocarbonyl-, hydroxy, (C1-C4)-alkoxy-(C1-C4)-alkyl-aminocarbonyl-,di-(C1-C4)--alkyl-amino (C1-C4)-alkoxy-(C1-C~)-alkyl-amino-carbonyl or 2 , 3-, 4-pyridylmethylamino-carbonyl group;
p ents (CH~)n , -CH~R4)-, ~CH2-CH(NH23- or -C~I2-CH(NH-CORa3- group;
R1, R2 and R3, that can be the same or diffPrent, are selected from the group consisting of hydrogen, hydroxy, (C1 C5) acyloxy, (C1--C4)--alkyl, (C1--C43--alkox~l, (C2 C~)--alkenyl, halogtan, (C1~C~)-acylamino, phenyl, phenoxy, t, . .~ ' .
'' ~
., .
~ 2 --imidazol-l-yl, carboxyl, (C1-C33-alkoxy-carbonyl, carboxy-(C1-C4)-alkyl;
R4 is a (C1-C4)-alkyl or a (C2-C4)-alkenyl group;
Ra is hydrogen or a (C1-C4)-alkyl group;
R6 is a (C1-C6)-alkyl group optionally substituted by (C1-C6)-alkoxy, carboxyl, ~C1-C4~-alkylamino, di-(C,-C4)-alkylamino, morpholin-N-yl, piperidin-l-yl, 4-~C1-C4)-alkyl-piperazin-l-yl, lC3-C6)-alkenyl, phenyl or phenyl-(C1-C6)-alkyl groups;
Rc is hydrogen or a (C1-C6)-alkyl, or (C6-C14)-ar-(C1-C4)-alkyl, or heteroalkyl group of a residue of a natural ~-aminoacid, and Rd and Re, which can be the same or dif~erent, are hydrogen, a (C1-C6)-alkyl optionally substituted by (C1-C6)-alkoxy, morpholin-N-yl, piperidin-l-yl, 4-(C1-C4)-alkyl-piperazin-l-yl, hydroxy-(C1-C4)-alkoxy-(C1-C4)-alkyl or di-(C1-C4~-alkylamino-(C1-C4)-alkoxy- (C~C4) -alkyl group or Rd and Re together with the nitrogen atom to which they are bonded form a heterocyclic ring selected ~rom the group consisting o~ morpholin-N-yl, piperidin-l-yl and 4-(C1-C4)-alkyl-piperazin-l-yl.
In the scope of the invention are also included pharmaceutically acceptable salts, optical antipodes, i.e.
the single enantiomers, mixtures of optical antipodes, diasteroisomers and mixtures o~ diasteroisomers of I compounds of formiula I.
I ~ The above mentioned carboxy groups are optionally sali~ied ¦: with an ammonium or alkaline cation.
The term halogen i5 to be understood to mean ~luorine, chlorine, bromine and iodine, but preferably bromine and l~ chlorine.
i~ ~ The aralkyl radical can be phenyl-~C~-C4)-alkyl or naphthyl (C1-C4) -alkyl .
1 ~:
1: .-::,.
:1. - ::
A (C1-C6)-alkyl, a (C6-C14~-ar-(C1-C4~-alkyl and a heteroalkyl residue o~ a natural ~-aminoacid means for example N-alanyl, N-valinyl, N-phenylalanyl, N-methionyl or N-histidinyl.
More particularly the present invention concerns addition salts with pharmaceutically acceptable bases, when in the compounds of formula I there is a free carboxylic group and addition salts with pharmaceutically acceptable acids, when in the compounds of formula I there is a basic organic portion.
Typical examples o~ non-toxic and pharmaceutically acceptable bases are organic bases, e.g. amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diisopropylamine, N-methyl-N-hexylamine, tromethamine, cyclohexylamine, N-methyl~N-cyclohexylamine, ~-I phenylethyleamine, B-phenylethylamine, N,N-I dimethylethanolamine, N,N-diethylethanolamine, ! ethylenediamine, piperidine, morpholine, pipera2ine, galactamine, N-methylglucamine, ephedrine, lysine, arginine ~l and inorganic bases such as hydroxides of alkaline and j alkaline-earth metals, as well as zinc and aluminum hydroxides.
Typical examples o~ non-toxic, pharmacologically acceptable acids are organic acids, such a~ acetic, formic, propionic, fumaric, tartaric, maleic, malic, malonic, benzoic, i salicylic, 3,4,5-trimethoxybenzoic, methanesulphonic, benzenesulphonic, camphorsulphonic, lactic, aspartic, glutammic, L- or D-2-phenyl-thiazolidine-5 carboxylic acids, cystine and cysteine; and inorganic acids such as l nitric, phosphoric, sulphuric, hydrochloric and hydrobromic j acids.
, According to the invention, alXyl, alkenyl, alkoxy group~
-, may have linear or branched chain.
,~ . .
.t Non-limitative examples of compounds of the invention are those whexein the group R1 , R~ (Ar) is phenyl, 2-hydroxyphenyl, 2- or 4-methoxyphenyl, 2-methoxy-4-allyl~phenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxy-4 hydroxyphenyl, 3,5-ditert.butoxy-4-hydroxy-phenyl, 4-acetamidophenyl, 4-ethoxycarbonylcarboxyamido-phenyl, 4-(imidazol-1-yl) 2-allyl-phenyl. B is a single bond or a 1,3-dioxolane-4,2-diyl, a 1,3-thioxolane-4,2-diyl, a 1,3-thioxolane-2,4-diyl or a 1,3-dioxolane-2,4-diyl group of the formulae:
o~l and X - R - T are one of the groups having the above reported formulae. . :
:~' ,:
j: : ~ ..
1 3~6668 Particularly preferred examples of compound~ of the ..
invention are: .
- ethyl 4-/4-(2-~etho~yphenoxy)-methyl-(E) (1,3)-dioxolane-2-yl/-3-oxa butanoate;
- 3-oxa-4-/4-(2-methoxyphenoxy)-methyl-(E)-(1,3) dioxolane-2-yl~-butanoic acid;
- 3-oxa-4-/4-(2-methoxyphenoxy9-mcthyl-(Z)-(1,3) dioxolane-2-yl/-butanoic acid; :
- 3-oxa-4-/4-(2-methoxyphenoxy)-methyl-(Z,E) (1,3)-dioxolane-2-yl/-butanoic acid;
- 3-oxa-4-/4-(3,5-diterbutyl-4-hydroxyphenoxy)-methyl (Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
l - 3-oxa-4-/-(3,5-dimethoxy-4~hydroxyphenoxy)methyl I (Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
! _ 3-oxa-4-/4-(3,4,5-trimethoxypheno~y)methyl-(Z,E) :l (193)-dioxolane-2-yl/--butanoic acid; -~
¦ - 3-oxa-4-/4-(2-methoxy-4-allyl-phenoxy~-methyl-(Z,E3-~ (1,3)-dioxolane-2-yl/-butanoic acid; .
- 3-oxa-4-/4-(4-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid; :~
- 3-thia-4-/4-(2 ~ethoxypherloxy~methyl-~Z,E)-dioxolane-2-yl~-butanoic acidl;
- 3-thi,~-4-/4-(2--phenoxy)methyl-(Z)-(1,3)-d;oxolane-2-yl/- butanoic acid; -~
. - 3-thia-4-/4-(4-methoxypheno~y)methyl-(Z,E3-(1,3)-l dioxolane-2-yl~-butanoic acid;
- 3-thia-4-/4-(2-methoxyphenoxy)methyl-(E)-(1,3)~
~ dioxolane-2-yl/-butanoic acid; -~ :
.!i _ 3-thia-4-/4-(~-hydroxyphenoxy)methyl-tZ,E)-(1~3)-¦~ dioxolane-2-yl/-butanoic acid; .
- 3-thia-4-/4-(3,'l,5-trimethoxyphenoxy3methyl-(Z,E)- :: .
3)-dioxolane-2-yl~-butanoic acid;
~:: - 3-thia-4-/'l-(3,5-dimetho~y-4-hydroxy-phenoxy)~ethyl-(Z,E)-~1,3)-dioxolane-2-yl/-butanoic acid;
.
". : , ... .
, - 3-thia-4-/4-(4-imidazol-1-yl-phenoxy)-methyl-(Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(3,5-diterbutyl-4-hydroxy-phenoxy)-methyl (Z,E)-t1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/-4-(4-aceta~idophenoxy~methyl-~Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(2-methoXY-4-allyl-phenoXy~nlethY
(Z,E)-(1,3)-dioxolane-2-yl/butanoic acid;
- 2-(acetylammino)-4-thia-5i4-(2-methoxyphenoxy) methyl(Z,E)-(1,3)-dioxolane-2-yl/-pentanoic acid;
- 2-(acetylamino)-4-thia-5/4-(4-methoxyphenoxy)methyl-(ZE)-(1,3)-dioxolane-2-yl/-pentanoic acid; ~ .
- 2S-/4-(2-~ethoxyphenoxy)methyl-~Z,E)~(1,3) dioxolane-7-yl/-methylthio-p~opionyl-~lycine;
- 2-(acetylamino)-4-thia-5/4-(4-methoxyphenoxy)methyl-(ZE)-(1,3)-dioxolane-2-yl/-pentanoic acid; ~ .
- 2S-/4-(2-~ethoxyphenoxy)methyl-~Z,E)~(1,3) dioxolane-7-yl/-methylthio-p~opionyl-~lycine;
- 3-thia-4/4-~2 Methoxyphenoxy)methyl-(Z,E)-(1,3)-thioxolane-2-yl/-butanoic acid; :~
- 3-thia-4/4-(4-methoxyphenoxy)-methyl-(Z,E)-(1,3)-thioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(3,4,5-trimethoxyphenoxy)methyl-(Z,E)-(1,3)-thioxolane-2 yl/-butanoic acid; -- 3-thia-4/4-~4-i~idazol-1-yl)-phenoxy)methyl-(Z9E) -(1,3)-thioxolane-2-yl/-butanoic acid; ~ :
- 3-thia-4-/4-(4-acetamido-phenoxy)methyl-(Z,E)- -~1,3)-thioxolan~-2-ylf-butanoic acid;
- 2-acetyla~ino-4-thia-5-/4-(2-methoxyphenoxy~ ~:
methyl-(Z,E)-(1,3)-thioxolane-2-ylJ-pentanoic acid;
2-acetylammino-4-thia-5-/4-(4-methoxyphenoxy~ ''., ~ethyl-(1,3)-thioxolane-2-yl/-pentanoic acid; ~ :
- 3-thia-4-t2-(2-methoxyphenoxy)methyl-~Z,E) :~
(1,3)-dioxolane-4-yl/-butanoic acid; ..
- methyl 2-(S)-acetylammino-4-thia-5-/2-(2-methoxy phenoxy)methyl-(Z,E)-(1,3)-dioxolane-4-yl/-pentanoate; : .
3-thia-5-(2-methoxyphenoxy)- pentanoic acid;
:: -: - 3-thia-5-(4-methoxyphenoxy~-pentanoic acid;
- 3-thia-5-(3,4,5-trimethoxyphenoxy)-pentanoic acid;
. '' -.
1 326~6~
- 3-thia-S-(3,5-dimethoxy-4-hydroxy-phenoxy)-pentanoic acid;
- 3-thia-5-(3,5-diterbutyl-4-hydroxy-phenoxy) pentanoic acid;
- 3-thia-5-(4-imidazol-1-yl-phenoxy~-pentanoic acid;
- 3-thia-5-(4-acetamido-phenoxy)-pentanoic acid;
- 3-thia-5-(2-methoxy-4-allyl-phenyl)-pentanoic acid;
- 1-(3-pyridyl-methylthio)methyl-4-(2-methoxyphenoxy)-methyl-(1,3)-dioxolane;
- (Z,E)-2-(3-pyridyl-methylthio)-methyl-4 (2-methoxyphenoxy)methyl-(1,3)-dioxolan~
- (Z,E)-4-(3-pyridyl-methylthio)methyl-2 -(2-methoxyphenoxy)methyl-(1,3)-dio.Yolane;
- ~Z,E)-2-(3-pyridyl-methylthio)-methyl-4 -(methoxyphenoxy)methyl-(1,3)-dio.Yolane;
- (Z,E)-2-(3-pyridyl-methylthio)-methyl-4- ~-(2-methoxypheno~y)-~ethyl-(1,3)-thioxolane; :
- 1-t3-pyridyl)-2-thia-4(4-methoxyphenoxy)butane;
3-pyridyl)-2-thia-4(-acetamido-phenoxy)butane;
3-pyridyl)-2-thia-4-/4-(imidazol-1-yl)-phenoxy/
butane; .:
(3-pyridyl)-2-thia 4-/2-methoxy-4-allyl-phenoxy~ :
butane;
- N-(3-pyridyl)-methyl,3-thia-4-/4-(2-r~ethoxyphenoxy)-:.
methyl-~is-trans-dioxolan-2-yl/-butanoic acid amide;
- N-(3-pyridyl~methyl, 3-thia-5-(2-methoxyphenoxy) pentanoic acid a~ide;
- N-~3-pyridyl)-3-thia-$-(4-methoxyphenoxy)-pentanoic acid amide;
- N~(3-py~idyl)-3-thia-5-(3,$,S-t~imetho.Yyphenoxy) pentanoic acid amide;
N-(3-pyridyl)~ethyl-3-thia-4-/4-(2-methoxyphenoxy)-methyl-lZ,:E)-(1,3)-dioxolan-2-yl/-butanoic acid a~ide;
- N-(3-pyridyl)~ethyl-3-thià-4-/'l-(4-methoxyphenoxy) '1 ~ methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide; :~.
., ~ .
~'j . .
; .~ ' ' ':
- 8 ~ 1 32666~
- N-(3-pyridyl)methyl-3-thia-4-/2-(2-methoxyphenoxy)-methyl-(Z,E)-(1,3)-dioxolan-4-yl/-butanoic acid;
- N-(3-pyridyl)methyl-3-thia 4-/4-(2-methoxyphenoxy3 methyl-(Z,E)-(1,3)-dioxolan-4-yl/-butanoic acid amide;
- N-(3-pyridyl)methyl-3-oxa-4-/4-(2-methoxyphenoxy ~iethyl-(Z,E)-(1,3)-dioxolan-2-yl/butanoic acid amide.
The compounds of the in-~ention of for~ula I are prepared by a process in which a compound of general for~ula II l R2 ~ (Ar)--O--CH2--(B~--C~2--Z(II) is reacted with a compound of general formula III
(T) - (R) - W (III) wherein R~ R1, R2, R3, Ar, B, T, are as above defined and one o~ Z and W is OH or -SH uhile the other is selected in the group of ~alo~en, thioacetate, acetate, mesylate or tosylate. The reaction between a compound of formula II and a compound of formula III
is c~rried out reacting stoichiometrical amounts of j these reagents in a suitable solvent in presence of a stoichiometrical a~ount or a slight excess of a base.
Suitable bases are alkaline or alkaline earth ~etals i hydroxides, carbonates or alcoholates. Suitable j solvents are methanol, ethanol, isopropanol, tert-butanol water or their mixtures.
Suitable bases can also be sodiu~ or potassiu~
hydrides in an inert solvent, such as hydrocarbon, ~ e.g. benzene, toluene, xylene, isooctane; an ether ~-j such as diethyl ether, diisopropyl ether, tert-butyl-ether, tetrahydrofuran, dioxane, ! dimethoxyethane or diglyme; di~ethylformamide or dimethylsulphoxide.
...;
~` . .
1 3266~
;' .
_ 9 -:
The reaction is carried out at a tempe~ature rangin~
rom -20 C to the solvent's reflux temperature, or any~ay, at temperatures not exceeding 100 C and the reaction time may range from one hour to some days.
When in the compounds of formulae II and III one of W
and Z is a free thiol group the reaction is carried out at room temperature in the presence of a slight ~olar excess of sodium ethoxide, preferably in ethanol, a~d usuall~ it is complete in 2 hours. When in the compounds of fotmulae II and III one of W and Z ;~
is OH, the reaction is preferabl) carried out at room temperature in an inert solvent, such as, for instance, dimethylformamide, ;n the presence of a slight molar excess of an alkaline hydride such as, for instance, sodium hydride and it is complete in 3 hol~rs.
Herebelou, fo~ the sake of shortness, symbols used previously for general formulae ~ill have the same meaning, ~nless other~ise indicated in the co~text.
Compounds of general formula II are kno~n and can be prepared folloulng ~kno~n methods. Particularly, the preparation of compounds~II wherein B is r \
~: . .~ .
.
! ' . ., ~.''.'.
- lo 1 32 ~ 6 68 is summarized in the following scheme 1 I_oH [o Rl ~ OH ~l ~ H Rl ¦ f R~(Ar)oH ~ ~ OH~ R~Ar)-O-CH2 ~ R~(Ar)-o-cH2 Z' R3 Cl ~3 R3 r (IV) (V) (VI) Rl ~ ~/ Z"' ~ ~ >-- I 2 ~;
/(~Ar)-o-cH2 ~ 2/ (Ar)-O-cH2 ' (VIII) (VII) .
wherein Z' is Cl, Br Z" îs OCOCH3 or S-COCH3 and Z''' is OH
¦ or SH.
¦ 5 The compounds IV, that are commercially available or 1 preparable according to known methods, are reacted with a 10% molar excess o~ a 3-halo-1,2-propandiol in the presence ~i of a base such as potassium or sodium hydroxide in water or ;~ sodium ethoxide in ethanol, accordiny to J. Org. Chem.
(1950~ 4986, for the preparation of dios of general formula V~ .
The compounds of general formula VI wherein Z' is halogen, :~
are prepared by reacting compounds V with a dimethyl- or I : ~ diethylace~ale of a ~-halogen aldehyde in the absence of a 601vent, at a temperature ranging from 50C to 150C, in j:: presence or not of catalytic amounts of p-koluensulfonic or -.
:J, sulphosalicylic acid ranging ~rom 10% molar to 25% molar with respect to the diol, or of an ion-exchange xesin in :~ acid form. :~:
~: ,::
; i .
., .
."
' ::' . .. .
: :
1 3~66~ ~
The reaction is carried out under a nitrogen atmosphere by heating a mixture of diol V with the suitable ~-halo-aldehyde acetale (in a molar excess from 10% to 150%) removing by distillation the formed alcohol. Preferably 20% molar excess of ~-chloro or ~-bromo acetaldehyde dimethyl (or diethyl-) acetale, 10% molar excess of p-toluensulphonic acid is reacted with the diol of formula V, at a temperature of i300C, distilling off methanol or ethanol.
The compounds VI wherein Z' is iodine can be easily obkained by treatment of a compound of formula VI wherein Z' is Cl, Br with an excess of potassium iodide according to known methods.
The trans~ormation of a compound of formula VI in a compound of formula VII wherein Z" is CH3COS or CH3COO- is carried out by treatment of a compound o~ formula ~I with an alkali acetate or thioacetate (in a molar excess from 100% to 300%). The reaction is carrie~ out in an inert solvent such as dimethylsulphoxide, dimethylformamide, dimethylacetamide, esamethylphosphotriamide, acetone, acetonitrile or water or their mixtures keeping the temperature in ~he range from UC to 100C, for a time from 1 hour to several days.
The halogen-acetate exchange is preferably carried out in dimethylsulphoxide, at fOC, with potassium acetate, in a 100~ molar excess, and the reaction is completed after 3 hours. The halogeno-thioacetate exchange preferably is ¦ carried ou~ in acetone, for instance, potassium thioacetate j 30 (300% excess) at room temperature, the reaction being ~ usually complete after a night.
,1, . ':
', .
.
,:~ .
- .
,~
.
. . .
The rompounds of general formula VIII wherein Z"' is OH or SH may be prepared, if desired, by hydrolysis of the corresponding acetates and thioacetates ~ith aqueous concentrated solutions of ammonium hydroxide, in a uater-miscible sol~ent such as dimethoxyethane, diglyme, triglyme, DMSO, TMF, or their mi~tures at room temperature in an inert gas atmosphere; the reaction time ~ay range from a fe~ minutes to some days. Preferred solvent is dimethoxymethane; the reaction has been usually completed after 3 hours, at room temperature and under inert gas at~osphere.
The compounds of general formula I ~herein B is a O~ .
o~
"'~
~ .
::: \, ;-, ~: , : : \ . :,,:
1,~;: ;',`,'~
- 1 32666~ :
can be obtained in accordance with scheme 2 (V3 ~ ~ (Ar)-O-C~2-CHO ~ H ~
IX X
l\(Ar)-O-CH2~ ~ R2\(Ar)-OCH2-CH ~ ':
R3 CH2-Z"' 3 C~2-Z' XII XI
':', Oxida~ion with sodiu~ periodate, in accordance with "Il farmaco" Ed. Sc. 9, 156, t19;6) of the diols X :~
gives the aldehyde IX ~hich can then be reacted with the com~ercia1ly available 3-halo-1,2-propane diols X
to give the dio~olanes XI.
The reaction of compounds X, wherein Z' is Cl or Br, :: with compounds :IX
(dioxolane f:or~ation) can be carried out by heating to the reflux~temperature a mixture sÇ the aldehyde IX
with~a ~olar~èxcess~(from 10~ to 50X) of the diol X
in an inert solvent such as benzene, toluene or xylene ~ :
in presence of an acid catalyst, such as p-toluene~sulphonic~acid, sulphosalicylic acid or an ioni-ex~change lesin in acid form by azeotropical removal of uater in ~a time raneing fro~ 1 to 12 hours. :
Ihe follow mg transformation of a compound of formula ~I (Z' = Cl or . :
Br) in a compound of formula XII (Z"' = OH and SH) is performed -~
~; : according to the above discussed procedure illustrating the conver- `
sion of a compound o~ formula VI in a compo~md of for~ula VIII.
-The preparation of compounds of formula I uherein B is a single bond is summarized in scheme 3 1 \ 1 IX 2 / 2 2 ~ 2 (Ar)-O-CH~CH2-Z
R XIII / XIVa ~
':' '.':
Rl \ ~ ' Rl ~ , .
R / (Ar)-OCH~-CH2-Z ~ R2 \ (Ar)-O CH2~CH2~Z
' ' R3 XIVc R3 XIVb IV :-uherein Z is tosylate or mesylate, Z' is Br or Cl and Z is SCOCH3 or SH.
The aldeh~des of general formula IX can be ~educed, if :
desired, by sodium boronhydride, to the correspondinK
alcohols XIII, according to kno~n techniques.
The compounds XIII can then be transformed intc the ---corresponding tosyl~tes or mesylates of for~ula IVa b~ ;
reaction~uith a mesyl or tosyl chloride of formula XIVa in the presence of a tertiary amine such as triethylamine or pyridine. Said reactions are ~ell known in chemical literature. Alternatively, alcohols ;
XIII can be transformed into the correspondin8 halides XIV~ ~herein Z''' is chlorine or broMine by trcatment respectively ~ith thionyl chloride or ~ith CDr~-triphcnylphosphine in accordancc uith Synth. -Comm. (1986) 16, 1926.
As above mentioned for th~ preparation of compounds Vlll, the compoun~s XIVb uherein ~ is SCOCH3 can be :,',',' ::
I 32666~
obtained by reacting both compounds XIVc and XIVa with potassium thioacetate. Thiols XI-'b, wherein Z is SH, can then be obtained by subsequent treat~ent with ammonium hydroxide-triphenylphosphine.
The preparation of compounds I uherein B is _~ S~
O ~ ' ' 1 ~ \
'i ~:: : ~ ' 1 32~68 is summarized in the following scheme 4 IX + ~H2_z~ ~ 2 / (Ar)-O-C~
3 ~H2-Z :~
XV . XVIa ~:~
R~ - (Ar)-O-C8 XVIb ~ :
~'''.':
The reaction between compounds, IX and the commercially available mercaptoalcohols XV, wherein Z' is Cl or Br, is .:.
carried out using reaction conditions similar to those above described in the reaction of compounds IX with diols .~ :
XO 1,3-oxathiolanes XVIa can then be transformed into the corresponding acetates, thioacetates, alcohols and thiols XVIb, wherein zVI is OCOCH3, SCOCH3, O~ or SH, according to the procedures above described in the ~
dioxolanes XI series~ :The compounds of general formula I , -wherein B is S~
Jo/ ;:
`; ~ ~ ...
, . .
~. .
1 32~668 can also be prepared according to scheme 5 (V~ ~ R - (Ar)-O-CH F ~ ~ R2 - ( Ar ) -OC~
3 XVII ~3 ~ II ~:
Rl r S Rl ~ r r ~H
\ ¦ O ~ Z~ \ ~ OH
R2 / (Ar)-OCH2 ~ 27 (Ar) O CH2 R3 3 . ~:
r XXa XIX I ~
S ,. . .
Rl~ Fo>~vii ' R2 / ~ Ar ~-O-~H2 R XXb us~in~ kno~rn procedures; monotosylates XVII are -~
obtained by~ selective ~onot~sylation of the primary :~
hydroxy ~roup of the diol V and are reacted ~ith a 1~
o1~r rAtio ~of potassium thioacetate and tetrabutyl ammoniu~ bromide (in a 300% ~olar excess in respect of the compounds XVII),~at ~room temperature in an inert ; I : solvent such as acetonitrlle or acetone to give compounds XVIII ~hich are then transformed into thiols ~ :
: X~IX by ammonolys~is.lSubsequent treatme~t of XIX ~ith halo-acetal~dehyde~ acetales ; affords the ::
:3-thioxolanes XXa, wherein Z ' is Cl or Br, whose halogen ; : :atom is~ transformed` :
. ., ~, ~ :.
-to give alcohols, acetates, thios, khioacetales, mesylates or p-toluensulphonates XXb wherein zvii is OCOCH3, CH3SO3-, CH3-C6H4-SO3-, -OH, -SCOCH3, -SH, using the procedure above 5 described in the case of dioxolanes VII and VIII.
To improve yields and to minimize consumption of basic reagents, the acetylation of the phenolic group, when one of R1, R2 or R3 is hydroxy may be carried out, if desired, using known procedures, by treatment with acetaldehyde, 10 then removing the acetate protecting group by mild hydrolysis with aqueous or ethanol solutions of sodium or potassium hydroxides.
The compounds of formula III are commercially available or ~ known substances that are prepared using known methods. So 33 15 for example, the compounds of formula III wherein T is 3-pyridyl, R is CH2 and W is chlorine can be obtained by I treating 3-pyridinmethanol with SOCl2; otherwise this latter f compound may be reacted with mesyl chloride and then with potassium thioacetate to give compounds of formula III
? 20 wherein T is 3-pyridyl, R is CH2 and W is thioacetate and/or thio after ammonolysis.
The transformation of compounds of formula III wherein W is Cl, Br or I into the corresponding alcohols or thiols can be carried out using the proceclures for the preparation of i 25 the compounds of general formu:La II.
The compounds of the gene~al formula I wherein T is an ester or amide group may be obtained starting from a compound of formula I wherein T is COOH by reaction with a suitable alcohol or amine using procedures well known in ! 30 the art.
The ccmpounds of the invention of general formula I are therapeutically useul substances, devoid of toxic effects ~¦ ~ and conveniently used as broncodilator, mucus-regulating i~ and antitussive agents. When administered by oral and ~ 35 i n t r a p e r i t o n e a 1 r o u t e t o m i c e :, .
~ ',:-. . .', . :
: .
1 32666~
and rats (~ale ~nd f~male) they are devoid of acute toxic eff~cts; LD50 rangin8 from 1 to 5 g/Kg ma~ be Measured .
The comp~unds of the invention are particularly useful as ~ntitussive, fluidifying of bronchial secretions and antiinflammat~ry a~ents.
Th~ ~b~ lity of ~ drug ~co ~o~y ehe erachao-bro~hial mucus ~cr~lon ~ lu~ d m~asurinçJ the 0xcx0tion o~
a dye~uf f lrl th~ ro~pir~coxy 'ree .
According ~ th0 proc0~ur~ of ~ watarl, ~Cago~him~
Da~ak~n ~klsn ~ hl, 27, 561 l~97~), Al~lrao ~ 8&
f0male ~alce ~r~ 0d by or~l rou~:e with tho ~rug a~d, 5 m~r~u~ a~'c0r~ wl~ch a O. S a~ueou~ uranl~
BC31Utis~ 0.1 r~/lOg body weight ~ by ~sub~ut~n~ou~
rQUt~. ~h~ a~l~n~ r~ ~acri~.0d 30 mlnutes ~gter; tho r~Bplr~Ory ~0~ 18 eXC~Re~ ~n~ ~ccur~to~y w~h~d. She w~hi~g ~lu~t~ LL ) ~r~ ~olle~ted ~n~ lu~t~d ~or th0 ura~ine corlt~n~ ~sing ~ $pectro~1uor~m~trl~
tecni~ue, Tharapeutica~ly active drug~ ~uch ~ brom~
~obrerol ~9 knowrl to incr0~ thu ur~n~ne cont~at :Ln ~he BA~ ' 8 in a do~e dependent way in ro~pect to the con~rol value~ (BAI'~ of ~nimal treace~ wlth vshicla3.
~ed phenol i~ o u~ed as dye~tuf ~; accord~ ng to the meth~d of ~ n~1~r et al., (3. Ph~m. Moth., 11, 151, 1984 ~ ~he ~ye~u~f i8 ~dmini~tered a~ a 5~ a~ueous su~pension ~rltxapsritosle~lly ( 500 mg/3sg) ~û minute~
~f ter oral tr~ment wlth t~e drug ~ or pla~e~o ~ . Albirlo Swiss male mie0 ~r~ u~d in thls test ~nd the animal~
i ~r~ killed 30 m~ut~s ater dye tre~tm~nt. The dye contsn~ in BAL's i3 evaluated spectrome~rically ~t 54 nm .
An increa6~d ~ed phe~ol ~scretion in B~L's after dru~
"~
, ~
..
,,, ",,," ,, " ,, : ,;
- 19a - 1 326668 tr~atment m~n~ ~timulation o~ mucus production.
In ~he following S~ble, the pharmacological re~ults, ob~ain~d wi~h reprs8entative exa~ples o~ ~he compounds of the invsntion:
- 3-thia-5-(2-methoxy-phenoxy)-pentanoic ~cid ~subs~anca ~); ::.
- N-~3~pyridyl)m0thyl-3-thia-5-(2-methoxy-phenoxy~
pentanoic acid amid~ ~substance B);
- 3-thla-4-C4-(2-M0thoxy-ph~no~y)~hyl-(2lE~-dloxo- - :
lan-2-yl~bu~anoic acid ~ub~t~ce ~
3-~ridyl~e hyl-3-thla-4 t4-~2-m~ hoxy-~honoxy)- ~
me~hyl~ (1,3)-d~oxol~n~2-yl3~ ta~o~ a~i~ a~nide ~ub~ ¢~
are r~pclr~ an~ comp~re~ wi~h tho~e obta~ne~ ~lth the above a~ ~d ri~oronc0 su~taaleai3: brom~aclne ~ ~u~t~nce E ~ 3n~ ~obr~rol g ~ub~ nco P' ) . ~:
"~.
~NCR~A. ~ O~ DY~T~IF~ 8~CR~TIûN IN
~V~ e~ altim~læ) SUBS~NC~ R~D ~NO~ U~A~INE ;~
mgtk~ o~ A ~ C ~ B ~ A ~ C D
25 25 1~ ~7 ~9 2~45 70 25 66 0 nt 50 50 73 ~3 ~20 6g 4a98 140 52 q32 50 54 lOO lO~ 126 14~ 179 ~3 69 13B 190 ioi 23~ 63 104 200 n~ n~c nt ~i~; nt 111 nt nt nt n'c n 144 nt - not te~te~ ref~rerJce substances '', ,,: ' '. ', ' - l9b - 1 326668 The red phenol tes'~ lso use ul for evalu~ting lon~-lasting a~1on ~f the investlg~tqd drug~. Infac~, a subs~ance can be ~dminl~tex~d 2, and 1/2 houx~ before the intraperi~on~al ad~ninistr~tion o~ the ~ed phenol rnark~r. If ~he anilTal~ ~r~ killed, as u~ual, half an houl after tha dye~tuff treatment, the ov~rall tiRle of drug action increase~ from 1 hr to 1 1/2 and 2 1/2 hrs respec~ ive~y .
~h2 r~e~U1~3 o:E thi~ ~'cu~y,~hor~in ~ull acti~e 1~ed ~o~e~ wer~ u~od, ~re rapor'ced ~n the ~ollowln~ t~q~lo.
TI~-COU~8E: :3F ~ INCP~A~ OF RBD PH~NOI~ E:XC~T~ON
t Y8- untre~t~ animal~ 3 ~UB~ANC~ mg/~ o~Jerall ex~erim~T~t hours ~o~
'~
A 100 10~ g8 62 ~Oû 12~ ~19 6 C 100 143 72 ~2 D : lû0 ~79 1~1 58 :P~EF~t~læN~;~ SU8STA~JC}~S
100 ~ ~1 21 ( ~ :
Th~ ~boYe Inen~ioned compounds of 'ch~ in~rentiorl ( sub- :
Rt~nces A-D ~ h~v~ been: also te~ted ~ antitu~give drugs. All th~ compous~ds pO~ 5 ~!1 good ~tivity; afte~ :
or~l ~dmini~ration ~ 50 mg/kg) a SO~ inhibltion of cough ( induc~d by ~ero~ol o~ a 30~ aqueous ~olution of citric acid) i~ me~ ured.
1 32666~
They are useful for treat~ent of bronchial ~
hyperreactivity that is tbought to be partially a :.
consequence of inflammatory conditions in the trach~
respiratory tree. ~ :
Infiltration of eosinophiles, desquamati~n of uide .
areas of epithelium, mucus hyp~rsecretion and b~onchial smooth muscle hyperplasia are aspects of thes~ inflammatory events. In animal ~odels, the compounds of the inven~ion are p~rticularly able to prevent ~ny of thes~ experi~entally ind~ced events.
For exampl~, the ~;ub~t~nce B ~ ~ter e . v . troatm~llt to ~naes~h~lzed guin0~-pig8 ~ubma ted to ~ ~o~d ~ob~cco-6moklng r~plr~o~a, in ~h~ rang~ o~ d.o~a~o~
f rom 5 to 30 mg/kç~ ablo to re~u~e th~
hyperr~ac~lY~ spa~mu~ in~uced ~y acotyl~hol~
c~lle~ag~ ~n do~o d~penden'c w~y. Po~i~lY0 ~e~Xonce sub~ne~ thi~ novel ~xp~rimen~al p~oco~uro Ar~
for ~xampl~: 6~ mo~hylpre~nisolon~ and ~o~lum ~ichromo~ te (l.m. adminlsgrat~on).
For the above mentioned therapeutical uses~ the co~pounds of the invention are formulated in phar~aceutical compositions, using conventional techniques and eccipien~s, as descri~ed in "Re~ington's Phar~aceutical Sciences' Handbook", Hack Publ. Co., New~ York, U.S.A. Exa~ples of said co~positions include capsules, tablets, packets, ~.
syrups, drinkable solutions, Supposieories, vials for I
parenteral or inhalatory ad~inistration, controlled-release forms, etc. ¦ -Dosages ulll ranee fro~ 100 and 2000 ~g pro day as total a~ount ~nd uill be administered in divided portions during che day, the specified dosage varying ~-dependine on the age, weight and conditions of the patient, as uell as on the administration route;
higher dosa8es even for long periods have no contraindications.
. :.
The invention uill be illustrated by the follo~ing non-limitinR examples.
.
1 32~668 A solution of 4-methoxyphenol (20 g) in absolute ethanol is slouly added at rooM temperature to a sol~tion of sodium ethoxide (160 ml) prepared "in situ" dissolving 4.2 g of sodium under nitrogen at~osphere. -~
After 30' a solution of 3-chloro-propane-1,2 diol (14.7 ~1) in absolute ethanol (20 ~l) is added and the resul~ing solution is for 4 ho~rs. After cooling and re~oval of salts by filtration, the ~ixture is dried and the resid~e is crystallized from diethyle~her. ~-29.B g of 3-(4 ~ethoxy)phenoxy-propane-1.2-diol, ~.p.
67-69 C, are obtained.
EXA~PLE 2 i Usin~ a suitable phenol in the procedure of exa~ple 1, by reaction uith 3-chloro-propane-1,2-diol the follou;ng propane-1l2-diols are obtained:
- 3(2-hydroxy-phenoxy)-propane-1.2-diol;
- 3(3-4-5-tri~ethoxy-phenoxy)-propane-1,2-diol; -~
- 3(3-5-dimethoxy-4-hydroxy-phenoxy)-propane-1,2-diol;
_ 3(3-5-ditertbutyl-4-hydroxy-phenoxy3-propane-~ 2-diol;
1~ - 3/4(i~idazol-1~yl)-phenoxy/-propane-1,2-diol;
- 3(4-aceta~ido-phenoxy)propane-1,2-diol;
- 3f2-~e~hoxy-4-alLyl-phenoxy/-propane-1,2-diol.
EXA~PLE 3 -3(4-methoxy-phenoxy)-propane-1,2-diol (65.3 8) is added to a ~olution of sodium periodate (60.5 g) in water (600 ml), cooled at 0 , and the re5ultin8 suspension has been stirred at 0 C for tuo hours. -~
After addition of ethyl acetate ( l l) the or8anic phase is separated, uashed uith uater, dried on sodium .
1 32666~
sulphate. Removal of the solvent under vacuum affords 2~4-methoxy phenoxy)ethanale (45 g) as a clear oil.
IR:~1725 c~ C03; ~35 cm ( ~ CH are OUT, adjacent 2H); NMR (CDCl3) ~ = 3,8 3H (s) OCH3; ~ =
- 3-thia-4/4-(4-methoxyphenoxy)-methyl-(Z,E)-(1,3)-thioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(3,4,5-trimethoxyphenoxy)methyl-(Z,E)-(1,3)-thioxolane-2 yl/-butanoic acid; -- 3-thia-4/4-~4-i~idazol-1-yl)-phenoxy)methyl-(Z9E) -(1,3)-thioxolane-2-yl/-butanoic acid; ~ :
- 3-thia-4-/4-(4-acetamido-phenoxy)methyl-(Z,E)- -~1,3)-thioxolan~-2-ylf-butanoic acid;
- 2-acetyla~ino-4-thia-5-/4-(2-methoxyphenoxy~ ~:
methyl-(Z,E)-(1,3)-thioxolane-2-ylJ-pentanoic acid;
2-acetylammino-4-thia-5-/4-(4-methoxyphenoxy~ ''., ~ethyl-(1,3)-thioxolane-2-yl/-pentanoic acid; ~ :
- 3-thia-4-t2-(2-methoxyphenoxy)methyl-~Z,E) :~
(1,3)-dioxolane-4-yl/-butanoic acid; ..
- methyl 2-(S)-acetylammino-4-thia-5-/2-(2-methoxy phenoxy)methyl-(Z,E)-(1,3)-dioxolane-4-yl/-pentanoate; : .
3-thia-5-(2-methoxyphenoxy)- pentanoic acid;
:: -: - 3-thia-5-(4-methoxyphenoxy~-pentanoic acid;
- 3-thia-5-(3,4,5-trimethoxyphenoxy)-pentanoic acid;
. '' -.
1 326~6~
- 3-thia-S-(3,5-dimethoxy-4-hydroxy-phenoxy)-pentanoic acid;
- 3-thia-5-(3,5-diterbutyl-4-hydroxy-phenoxy) pentanoic acid;
- 3-thia-5-(4-imidazol-1-yl-phenoxy~-pentanoic acid;
- 3-thia-5-(4-acetamido-phenoxy)-pentanoic acid;
- 3-thia-5-(2-methoxy-4-allyl-phenyl)-pentanoic acid;
- 1-(3-pyridyl-methylthio)methyl-4-(2-methoxyphenoxy)-methyl-(1,3)-dioxolane;
- (Z,E)-2-(3-pyridyl-methylthio)-methyl-4 (2-methoxyphenoxy)methyl-(1,3)-dioxolan~
- (Z,E)-4-(3-pyridyl-methylthio)methyl-2 -(2-methoxyphenoxy)methyl-(1,3)-dio.Yolane;
- ~Z,E)-2-(3-pyridyl-methylthio)-methyl-4 -(methoxyphenoxy)methyl-(1,3)-dio.Yolane;
- (Z,E)-2-(3-pyridyl-methylthio)-methyl-4- ~-(2-methoxypheno~y)-~ethyl-(1,3)-thioxolane; :
- 1-t3-pyridyl)-2-thia-4(4-methoxyphenoxy)butane;
3-pyridyl)-2-thia-4(-acetamido-phenoxy)butane;
3-pyridyl)-2-thia-4-/4-(imidazol-1-yl)-phenoxy/
butane; .:
(3-pyridyl)-2-thia 4-/2-methoxy-4-allyl-phenoxy~ :
butane;
- N-(3-pyridyl)-methyl,3-thia-4-/4-(2-r~ethoxyphenoxy)-:.
methyl-~is-trans-dioxolan-2-yl/-butanoic acid amide;
- N-(3-pyridyl~methyl, 3-thia-5-(2-methoxyphenoxy) pentanoic acid a~ide;
- N-~3-pyridyl)-3-thia-$-(4-methoxyphenoxy)-pentanoic acid amide;
- N~(3-py~idyl)-3-thia-5-(3,$,S-t~imetho.Yyphenoxy) pentanoic acid amide;
N-(3-pyridyl)~ethyl-3-thia-4-/4-(2-methoxyphenoxy)-methyl-lZ,:E)-(1,3)-dioxolan-2-yl/-butanoic acid a~ide;
- N-(3-pyridyl)~ethyl-3-thià-4-/'l-(4-methoxyphenoxy) '1 ~ methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide; :~.
., ~ .
~'j . .
; .~ ' ' ':
- 8 ~ 1 32666~
- N-(3-pyridyl)methyl-3-thia-4-/2-(2-methoxyphenoxy)-methyl-(Z,E)-(1,3)-dioxolan-4-yl/-butanoic acid;
- N-(3-pyridyl)methyl-3-thia 4-/4-(2-methoxyphenoxy3 methyl-(Z,E)-(1,3)-dioxolan-4-yl/-butanoic acid amide;
- N-(3-pyridyl)methyl-3-oxa-4-/4-(2-methoxyphenoxy ~iethyl-(Z,E)-(1,3)-dioxolan-2-yl/butanoic acid amide.
The compounds of the in-~ention of for~ula I are prepared by a process in which a compound of general for~ula II l R2 ~ (Ar)--O--CH2--(B~--C~2--Z(II) is reacted with a compound of general formula III
(T) - (R) - W (III) wherein R~ R1, R2, R3, Ar, B, T, are as above defined and one o~ Z and W is OH or -SH uhile the other is selected in the group of ~alo~en, thioacetate, acetate, mesylate or tosylate. The reaction between a compound of formula II and a compound of formula III
is c~rried out reacting stoichiometrical amounts of j these reagents in a suitable solvent in presence of a stoichiometrical a~ount or a slight excess of a base.
Suitable bases are alkaline or alkaline earth ~etals i hydroxides, carbonates or alcoholates. Suitable j solvents are methanol, ethanol, isopropanol, tert-butanol water or their mixtures.
Suitable bases can also be sodiu~ or potassiu~
hydrides in an inert solvent, such as hydrocarbon, ~ e.g. benzene, toluene, xylene, isooctane; an ether ~-j such as diethyl ether, diisopropyl ether, tert-butyl-ether, tetrahydrofuran, dioxane, ! dimethoxyethane or diglyme; di~ethylformamide or dimethylsulphoxide.
...;
~` . .
1 3266~
;' .
_ 9 -:
The reaction is carried out at a tempe~ature rangin~
rom -20 C to the solvent's reflux temperature, or any~ay, at temperatures not exceeding 100 C and the reaction time may range from one hour to some days.
When in the compounds of formulae II and III one of W
and Z is a free thiol group the reaction is carried out at room temperature in the presence of a slight ~olar excess of sodium ethoxide, preferably in ethanol, a~d usuall~ it is complete in 2 hours. When in the compounds of fotmulae II and III one of W and Z ;~
is OH, the reaction is preferabl) carried out at room temperature in an inert solvent, such as, for instance, dimethylformamide, ;n the presence of a slight molar excess of an alkaline hydride such as, for instance, sodium hydride and it is complete in 3 hol~rs.
Herebelou, fo~ the sake of shortness, symbols used previously for general formulae ~ill have the same meaning, ~nless other~ise indicated in the co~text.
Compounds of general formula II are kno~n and can be prepared folloulng ~kno~n methods. Particularly, the preparation of compounds~II wherein B is r \
~: . .~ .
.
! ' . ., ~.''.'.
- lo 1 32 ~ 6 68 is summarized in the following scheme 1 I_oH [o Rl ~ OH ~l ~ H Rl ¦ f R~(Ar)oH ~ ~ OH~ R~Ar)-O-CH2 ~ R~(Ar)-o-cH2 Z' R3 Cl ~3 R3 r (IV) (V) (VI) Rl ~ ~/ Z"' ~ ~ >-- I 2 ~;
/(~Ar)-o-cH2 ~ 2/ (Ar)-O-cH2 ' (VIII) (VII) .
wherein Z' is Cl, Br Z" îs OCOCH3 or S-COCH3 and Z''' is OH
¦ or SH.
¦ 5 The compounds IV, that are commercially available or 1 preparable according to known methods, are reacted with a 10% molar excess o~ a 3-halo-1,2-propandiol in the presence ~i of a base such as potassium or sodium hydroxide in water or ;~ sodium ethoxide in ethanol, accordiny to J. Org. Chem.
(1950~ 4986, for the preparation of dios of general formula V~ .
The compounds of general formula VI wherein Z' is halogen, :~
are prepared by reacting compounds V with a dimethyl- or I : ~ diethylace~ale of a ~-halogen aldehyde in the absence of a 601vent, at a temperature ranging from 50C to 150C, in j:: presence or not of catalytic amounts of p-koluensulfonic or -.
:J, sulphosalicylic acid ranging ~rom 10% molar to 25% molar with respect to the diol, or of an ion-exchange xesin in :~ acid form. :~:
~: ,::
; i .
., .
."
' ::' . .. .
: :
1 3~66~ ~
The reaction is carried out under a nitrogen atmosphere by heating a mixture of diol V with the suitable ~-halo-aldehyde acetale (in a molar excess from 10% to 150%) removing by distillation the formed alcohol. Preferably 20% molar excess of ~-chloro or ~-bromo acetaldehyde dimethyl (or diethyl-) acetale, 10% molar excess of p-toluensulphonic acid is reacted with the diol of formula V, at a temperature of i300C, distilling off methanol or ethanol.
The compounds VI wherein Z' is iodine can be easily obkained by treatment of a compound of formula VI wherein Z' is Cl, Br with an excess of potassium iodide according to known methods.
The trans~ormation of a compound of formula VI in a compound of formula VII wherein Z" is CH3COS or CH3COO- is carried out by treatment of a compound o~ formula ~I with an alkali acetate or thioacetate (in a molar excess from 100% to 300%). The reaction is carrie~ out in an inert solvent such as dimethylsulphoxide, dimethylformamide, dimethylacetamide, esamethylphosphotriamide, acetone, acetonitrile or water or their mixtures keeping the temperature in ~he range from UC to 100C, for a time from 1 hour to several days.
The halogen-acetate exchange is preferably carried out in dimethylsulphoxide, at fOC, with potassium acetate, in a 100~ molar excess, and the reaction is completed after 3 hours. The halogeno-thioacetate exchange preferably is ¦ carried ou~ in acetone, for instance, potassium thioacetate j 30 (300% excess) at room temperature, the reaction being ~ usually complete after a night.
,1, . ':
', .
.
,:~ .
- .
,~
.
. . .
The rompounds of general formula VIII wherein Z"' is OH or SH may be prepared, if desired, by hydrolysis of the corresponding acetates and thioacetates ~ith aqueous concentrated solutions of ammonium hydroxide, in a uater-miscible sol~ent such as dimethoxyethane, diglyme, triglyme, DMSO, TMF, or their mi~tures at room temperature in an inert gas atmosphere; the reaction time ~ay range from a fe~ minutes to some days. Preferred solvent is dimethoxymethane; the reaction has been usually completed after 3 hours, at room temperature and under inert gas at~osphere.
The compounds of general formula I ~herein B is a O~ .
o~
"'~
~ .
::: \, ;-, ~: , : : \ . :,,:
1,~;: ;',`,'~
- 1 32666~ :
can be obtained in accordance with scheme 2 (V3 ~ ~ (Ar)-O-C~2-CHO ~ H ~
IX X
l\(Ar)-O-CH2~ ~ R2\(Ar)-OCH2-CH ~ ':
R3 CH2-Z"' 3 C~2-Z' XII XI
':', Oxida~ion with sodiu~ periodate, in accordance with "Il farmaco" Ed. Sc. 9, 156, t19;6) of the diols X :~
gives the aldehyde IX ~hich can then be reacted with the com~ercia1ly available 3-halo-1,2-propane diols X
to give the dio~olanes XI.
The reaction of compounds X, wherein Z' is Cl or Br, :: with compounds :IX
(dioxolane f:or~ation) can be carried out by heating to the reflux~temperature a mixture sÇ the aldehyde IX
with~a ~olar~èxcess~(from 10~ to 50X) of the diol X
in an inert solvent such as benzene, toluene or xylene ~ :
in presence of an acid catalyst, such as p-toluene~sulphonic~acid, sulphosalicylic acid or an ioni-ex~change lesin in acid form by azeotropical removal of uater in ~a time raneing fro~ 1 to 12 hours. :
Ihe follow mg transformation of a compound of formula ~I (Z' = Cl or . :
Br) in a compound of formula XII (Z"' = OH and SH) is performed -~
~; : according to the above discussed procedure illustrating the conver- `
sion of a compound o~ formula VI in a compo~md of for~ula VIII.
-The preparation of compounds of formula I uherein B is a single bond is summarized in scheme 3 1 \ 1 IX 2 / 2 2 ~ 2 (Ar)-O-CH~CH2-Z
R XIII / XIVa ~
':' '.':
Rl \ ~ ' Rl ~ , .
R / (Ar)-OCH~-CH2-Z ~ R2 \ (Ar)-O CH2~CH2~Z
' ' R3 XIVc R3 XIVb IV :-uherein Z is tosylate or mesylate, Z' is Br or Cl and Z is SCOCH3 or SH.
The aldeh~des of general formula IX can be ~educed, if :
desired, by sodium boronhydride, to the correspondinK
alcohols XIII, according to kno~n techniques.
The compounds XIII can then be transformed intc the ---corresponding tosyl~tes or mesylates of for~ula IVa b~ ;
reaction~uith a mesyl or tosyl chloride of formula XIVa in the presence of a tertiary amine such as triethylamine or pyridine. Said reactions are ~ell known in chemical literature. Alternatively, alcohols ;
XIII can be transformed into the correspondin8 halides XIV~ ~herein Z''' is chlorine or broMine by trcatment respectively ~ith thionyl chloride or ~ith CDr~-triphcnylphosphine in accordancc uith Synth. -Comm. (1986) 16, 1926.
As above mentioned for th~ preparation of compounds Vlll, the compoun~s XIVb uherein ~ is SCOCH3 can be :,',',' ::
I 32666~
obtained by reacting both compounds XIVc and XIVa with potassium thioacetate. Thiols XI-'b, wherein Z is SH, can then be obtained by subsequent treat~ent with ammonium hydroxide-triphenylphosphine.
The preparation of compounds I uherein B is _~ S~
O ~ ' ' 1 ~ \
'i ~:: : ~ ' 1 32~68 is summarized in the following scheme 4 IX + ~H2_z~ ~ 2 / (Ar)-O-C~
3 ~H2-Z :~
XV . XVIa ~:~
R~ - (Ar)-O-C8 XVIb ~ :
~'''.':
The reaction between compounds, IX and the commercially available mercaptoalcohols XV, wherein Z' is Cl or Br, is .:.
carried out using reaction conditions similar to those above described in the reaction of compounds IX with diols .~ :
XO 1,3-oxathiolanes XVIa can then be transformed into the corresponding acetates, thioacetates, alcohols and thiols XVIb, wherein zVI is OCOCH3, SCOCH3, O~ or SH, according to the procedures above described in the ~
dioxolanes XI series~ :The compounds of general formula I , -wherein B is S~
Jo/ ;:
`; ~ ~ ...
, . .
~. .
1 32~668 can also be prepared according to scheme 5 (V~ ~ R - (Ar)-O-CH F ~ ~ R2 - ( Ar ) -OC~
3 XVII ~3 ~ II ~:
Rl r S Rl ~ r r ~H
\ ¦ O ~ Z~ \ ~ OH
R2 / (Ar)-OCH2 ~ 27 (Ar) O CH2 R3 3 . ~:
r XXa XIX I ~
S ,. . .
Rl~ Fo>~vii ' R2 / ~ Ar ~-O-~H2 R XXb us~in~ kno~rn procedures; monotosylates XVII are -~
obtained by~ selective ~onot~sylation of the primary :~
hydroxy ~roup of the diol V and are reacted ~ith a 1~
o1~r rAtio ~of potassium thioacetate and tetrabutyl ammoniu~ bromide (in a 300% ~olar excess in respect of the compounds XVII),~at ~room temperature in an inert ; I : solvent such as acetonitrlle or acetone to give compounds XVIII ~hich are then transformed into thiols ~ :
: X~IX by ammonolys~is.lSubsequent treatme~t of XIX ~ith halo-acetal~dehyde~ acetales ; affords the ::
:3-thioxolanes XXa, wherein Z ' is Cl or Br, whose halogen ; : :atom is~ transformed` :
. ., ~, ~ :.
-to give alcohols, acetates, thios, khioacetales, mesylates or p-toluensulphonates XXb wherein zvii is OCOCH3, CH3SO3-, CH3-C6H4-SO3-, -OH, -SCOCH3, -SH, using the procedure above 5 described in the case of dioxolanes VII and VIII.
To improve yields and to minimize consumption of basic reagents, the acetylation of the phenolic group, when one of R1, R2 or R3 is hydroxy may be carried out, if desired, using known procedures, by treatment with acetaldehyde, 10 then removing the acetate protecting group by mild hydrolysis with aqueous or ethanol solutions of sodium or potassium hydroxides.
The compounds of formula III are commercially available or ~ known substances that are prepared using known methods. So 33 15 for example, the compounds of formula III wherein T is 3-pyridyl, R is CH2 and W is chlorine can be obtained by I treating 3-pyridinmethanol with SOCl2; otherwise this latter f compound may be reacted with mesyl chloride and then with potassium thioacetate to give compounds of formula III
? 20 wherein T is 3-pyridyl, R is CH2 and W is thioacetate and/or thio after ammonolysis.
The transformation of compounds of formula III wherein W is Cl, Br or I into the corresponding alcohols or thiols can be carried out using the proceclures for the preparation of i 25 the compounds of general formu:La II.
The compounds of the gene~al formula I wherein T is an ester or amide group may be obtained starting from a compound of formula I wherein T is COOH by reaction with a suitable alcohol or amine using procedures well known in ! 30 the art.
The ccmpounds of the invention of general formula I are therapeutically useul substances, devoid of toxic effects ~¦ ~ and conveniently used as broncodilator, mucus-regulating i~ and antitussive agents. When administered by oral and ~ 35 i n t r a p e r i t o n e a 1 r o u t e t o m i c e :, .
~ ',:-. . .', . :
: .
1 32666~
and rats (~ale ~nd f~male) they are devoid of acute toxic eff~cts; LD50 rangin8 from 1 to 5 g/Kg ma~ be Measured .
The comp~unds of the invention are particularly useful as ~ntitussive, fluidifying of bronchial secretions and antiinflammat~ry a~ents.
Th~ ~b~ lity of ~ drug ~co ~o~y ehe erachao-bro~hial mucus ~cr~lon ~ lu~ d m~asurinçJ the 0xcx0tion o~
a dye~uf f lrl th~ ro~pir~coxy 'ree .
According ~ th0 proc0~ur~ of ~ watarl, ~Cago~him~
Da~ak~n ~klsn ~ hl, 27, 561 l~97~), Al~lrao ~ 8&
f0male ~alce ~r~ 0d by or~l rou~:e with tho ~rug a~d, 5 m~r~u~ a~'c0r~ wl~ch a O. S a~ueou~ uranl~
BC31Utis~ 0.1 r~/lOg body weight ~ by ~sub~ut~n~ou~
rQUt~. ~h~ a~l~n~ r~ ~acri~.0d 30 mlnutes ~gter; tho r~Bplr~Ory ~0~ 18 eXC~Re~ ~n~ ~ccur~to~y w~h~d. She w~hi~g ~lu~t~ LL ) ~r~ ~olle~ted ~n~ lu~t~d ~or th0 ura~ine corlt~n~ ~sing ~ $pectro~1uor~m~trl~
tecni~ue, Tharapeutica~ly active drug~ ~uch ~ brom~
~obrerol ~9 knowrl to incr0~ thu ur~n~ne cont~at :Ln ~he BA~ ' 8 in a do~e dependent way in ro~pect to the con~rol value~ (BAI'~ of ~nimal treace~ wlth vshicla3.
~ed phenol i~ o u~ed as dye~tuf ~; accord~ ng to the meth~d of ~ n~1~r et al., (3. Ph~m. Moth., 11, 151, 1984 ~ ~he ~ye~u~f i8 ~dmini~tered a~ a 5~ a~ueous su~pension ~rltxapsritosle~lly ( 500 mg/3sg) ~û minute~
~f ter oral tr~ment wlth t~e drug ~ or pla~e~o ~ . Albirlo Swiss male mie0 ~r~ u~d in thls test ~nd the animal~
i ~r~ killed 30 m~ut~s ater dye tre~tm~nt. The dye contsn~ in BAL's i3 evaluated spectrome~rically ~t 54 nm .
An increa6~d ~ed phe~ol ~scretion in B~L's after dru~
"~
, ~
..
,,, ",,," ,, " ,, : ,;
- 19a - 1 326668 tr~atment m~n~ ~timulation o~ mucus production.
In ~he following S~ble, the pharmacological re~ults, ob~ain~d wi~h reprs8entative exa~ples o~ ~he compounds of the invsntion:
- 3-thia-5-(2-methoxy-phenoxy)-pentanoic ~cid ~subs~anca ~); ::.
- N-~3~pyridyl)m0thyl-3-thia-5-(2-methoxy-phenoxy~
pentanoic acid amid~ ~substance B);
- 3-thla-4-C4-(2-M0thoxy-ph~no~y)~hyl-(2lE~-dloxo- - :
lan-2-yl~bu~anoic acid ~ub~t~ce ~
3-~ridyl~e hyl-3-thla-4 t4-~2-m~ hoxy-~honoxy)- ~
me~hyl~ (1,3)-d~oxol~n~2-yl3~ ta~o~ a~i~ a~nide ~ub~ ¢~
are r~pclr~ an~ comp~re~ wi~h tho~e obta~ne~ ~lth the above a~ ~d ri~oronc0 su~taaleai3: brom~aclne ~ ~u~t~nce E ~ 3n~ ~obr~rol g ~ub~ nco P' ) . ~:
"~.
~NCR~A. ~ O~ DY~T~IF~ 8~CR~TIûN IN
~V~ e~ altim~læ) SUBS~NC~ R~D ~NO~ U~A~INE ;~
mgtk~ o~ A ~ C ~ B ~ A ~ C D
25 25 1~ ~7 ~9 2~45 70 25 66 0 nt 50 50 73 ~3 ~20 6g 4a98 140 52 q32 50 54 lOO lO~ 126 14~ 179 ~3 69 13B 190 ioi 23~ 63 104 200 n~ n~c nt ~i~; nt 111 nt nt nt n'c n 144 nt - not te~te~ ref~rerJce substances '', ,,: ' '. ', ' - l9b - 1 326668 The red phenol tes'~ lso use ul for evalu~ting lon~-lasting a~1on ~f the investlg~tqd drug~. Infac~, a subs~ance can be ~dminl~tex~d 2, and 1/2 houx~ before the intraperi~on~al ad~ninistr~tion o~ the ~ed phenol rnark~r. If ~he anilTal~ ~r~ killed, as u~ual, half an houl after tha dye~tuff treatment, the ov~rall tiRle of drug action increase~ from 1 hr to 1 1/2 and 2 1/2 hrs respec~ ive~y .
~h2 r~e~U1~3 o:E thi~ ~'cu~y,~hor~in ~ull acti~e 1~ed ~o~e~ wer~ u~od, ~re rapor'ced ~n the ~ollowln~ t~q~lo.
TI~-COU~8E: :3F ~ INCP~A~ OF RBD PH~NOI~ E:XC~T~ON
t Y8- untre~t~ animal~ 3 ~UB~ANC~ mg/~ o~Jerall ex~erim~T~t hours ~o~
'~
A 100 10~ g8 62 ~Oû 12~ ~19 6 C 100 143 72 ~2 D : lû0 ~79 1~1 58 :P~EF~t~læN~;~ SU8STA~JC}~S
100 ~ ~1 21 ( ~ :
Th~ ~boYe Inen~ioned compounds of 'ch~ in~rentiorl ( sub- :
Rt~nces A-D ~ h~v~ been: also te~ted ~ antitu~give drugs. All th~ compous~ds pO~ 5 ~!1 good ~tivity; afte~ :
or~l ~dmini~ration ~ 50 mg/kg) a SO~ inhibltion of cough ( induc~d by ~ero~ol o~ a 30~ aqueous ~olution of citric acid) i~ me~ ured.
1 32666~
They are useful for treat~ent of bronchial ~
hyperreactivity that is tbought to be partially a :.
consequence of inflammatory conditions in the trach~
respiratory tree. ~ :
Infiltration of eosinophiles, desquamati~n of uide .
areas of epithelium, mucus hyp~rsecretion and b~onchial smooth muscle hyperplasia are aspects of thes~ inflammatory events. In animal ~odels, the compounds of the inven~ion are p~rticularly able to prevent ~ny of thes~ experi~entally ind~ced events.
For exampl~, the ~;ub~t~nce B ~ ~ter e . v . troatm~llt to ~naes~h~lzed guin0~-pig8 ~ubma ted to ~ ~o~d ~ob~cco-6moklng r~plr~o~a, in ~h~ rang~ o~ d.o~a~o~
f rom 5 to 30 mg/kç~ ablo to re~u~e th~
hyperr~ac~lY~ spa~mu~ in~uced ~y acotyl~hol~
c~lle~ag~ ~n do~o d~penden'c w~y. Po~i~lY0 ~e~Xonce sub~ne~ thi~ novel ~xp~rimen~al p~oco~uro Ar~
for ~xampl~: 6~ mo~hylpre~nisolon~ and ~o~lum ~ichromo~ te (l.m. adminlsgrat~on).
For the above mentioned therapeutical uses~ the co~pounds of the invention are formulated in phar~aceutical compositions, using conventional techniques and eccipien~s, as descri~ed in "Re~ington's Phar~aceutical Sciences' Handbook", Hack Publ. Co., New~ York, U.S.A. Exa~ples of said co~positions include capsules, tablets, packets, ~.
syrups, drinkable solutions, Supposieories, vials for I
parenteral or inhalatory ad~inistration, controlled-release forms, etc. ¦ -Dosages ulll ranee fro~ 100 and 2000 ~g pro day as total a~ount ~nd uill be administered in divided portions during che day, the specified dosage varying ~-dependine on the age, weight and conditions of the patient, as uell as on the administration route;
higher dosa8es even for long periods have no contraindications.
. :.
The invention uill be illustrated by the follo~ing non-limitinR examples.
.
1 32~668 A solution of 4-methoxyphenol (20 g) in absolute ethanol is slouly added at rooM temperature to a sol~tion of sodium ethoxide (160 ml) prepared "in situ" dissolving 4.2 g of sodium under nitrogen at~osphere. -~
After 30' a solution of 3-chloro-propane-1,2 diol (14.7 ~1) in absolute ethanol (20 ~l) is added and the resul~ing solution is for 4 ho~rs. After cooling and re~oval of salts by filtration, the ~ixture is dried and the resid~e is crystallized from diethyle~her. ~-29.B g of 3-(4 ~ethoxy)phenoxy-propane-1.2-diol, ~.p.
67-69 C, are obtained.
EXA~PLE 2 i Usin~ a suitable phenol in the procedure of exa~ple 1, by reaction uith 3-chloro-propane-1,2-diol the follou;ng propane-1l2-diols are obtained:
- 3(2-hydroxy-phenoxy)-propane-1.2-diol;
- 3(3-4-5-tri~ethoxy-phenoxy)-propane-1,2-diol; -~
- 3(3-5-dimethoxy-4-hydroxy-phenoxy)-propane-1,2-diol;
_ 3(3-5-ditertbutyl-4-hydroxy-phenoxy3-propane-~ 2-diol;
1~ - 3/4(i~idazol-1~yl)-phenoxy/-propane-1,2-diol;
- 3(4-aceta~ido-phenoxy)propane-1,2-diol;
- 3f2-~e~hoxy-4-alLyl-phenoxy/-propane-1,2-diol.
EXA~PLE 3 -3(4-methoxy-phenoxy)-propane-1,2-diol (65.3 8) is added to a ~olution of sodium periodate (60.5 g) in water (600 ml), cooled at 0 , and the re5ultin8 suspension has been stirred at 0 C for tuo hours. -~
After addition of ethyl acetate ( l l) the or8anic phase is separated, uashed uith uater, dried on sodium .
1 32666~
sulphate. Removal of the solvent under vacuum affords 2~4-methoxy phenoxy)ethanale (45 g) as a clear oil.
IR:~1725 c~ C03; ~35 cm ( ~ CH are OUT, adjacent 2H); NMR (CDCl3) ~ = 3,8 3H (s) OCH3; ~ =
4,5 2H (s) -CH2-CHO- ; ~ = 9,8, lH (s) CHO.
EXA~PLE 4 Using a suitable 3-substituted-propane-1,2-diol of the ex~mple 2 in the procedure of example 3, the follouing 2-su~stituted ethanales are obtained:
- 2(2-methoxyphenoxy)etha~ale (~.p.65-67 C);
- 2~3,4,5-trimethoxypheno~y)ethanale;
- 2/4-(imida~ol-1-yl)phenoxy~-ethanale;
- 2-/2-methoxy-4-allyl-phenoxy/-ethanale.
. .:
EXA~PLE 5 Sodiu~ borohydride (3.78 g) is added to a solution of 2~2-met~oxyphæinoxyethanale (16.6 ~) in methanol (20 ml) cooled at O C, in small portions, keeping the tem-perature under 10 C. After 30' at 10 C the reaction ~ixture is poured in aqueous NaH2P04 30~ (200 ~l) and extracted with ethyl acetate ( 3 x 100 ml). The o~ganic extracts are ~ashed ~ith ~ater, dried on Na2S06 and concentrated under vacuum to give 2-(4-~ethoxy-pheno~y)ethanol-2-(4-methoxypheno~y) (13.5 ~) as a yellou oil (NMR (CDCl3) ~ = 2,8.3,7, 1H
(m) OH disappears with D20; IR: = ~ 3000-3600 cm OH).
A solution of 5~ 8 of the above product in dichloroethane (40 ml), cooled at O C, is treated ~ith triethylamine (4.6 ml) and uith a solution of methanesulphonyl chloride (2.55 ml~ in dichloroethane which is then addcd dropuise. The reaction mixture is . - ::, stirred for 3 hours at room temperature and then ~iltered.
':
-- 22 - 132~668 The filtrate is washed with water, 5~ii aqueous NaHCO3 and again with water. After anhydrification on sodium sulphate and removal of the solvent under vacuum the residue is crystallized from isopropyl ether to give 5.4 g of 2-(2-methoxyphenoxy)-ethylmethanesulphonate, m.p. 73-76CO
After reduction of a suitable 2-substituted ethanale of the sxamples 3 and 4 with NaBH4 and after reaction with methane sulphonyl chloride, according to example 5, the following methanesulphonates are obtained:
- 2-/2-methoxy-4-allyl-phenoxy/-ethyl methanesulphonate;
- 2(4-methoxyphenoxy)ethyl methanesulphonate;
- 2-(4-imidazol-1-yl-phenoxy)ethyl methanesulphonate;
- 2-(4-acetamidophenoxy)ethyl methanesulphonate.
~XaMPLE 7 A solution of 3-(2-methoxy-phenoxy)-propane-1,2-diol (4.7 g) in pyridine, cooled at 5-10C, is treated under stirring with a solution o p-toluensulphonylchloride (4.5 g) in benzene (70 ml). The reaction mixture is stirred overnight at room temperature, then it i5 washed with 2N HCl (3 x 100 ml3 and with waterl dried on Na2SO4 and evaporated to drynesiqi in vacuum. The oily residue is purified by column chromatography (silica gel - 230-400 mesh hexane/ AcOEt =
3J1) to yield 5 y of 3-(2-methoxy-phenoxy)-2-hydroxy-1-propyl p-toluensulphonate (oil, NMR (-CDc13): = 2,4 3H (s) CH3SO2; = 3,75-4,4 5H (m) OCH3 + OCH2).
Potassium thioacetate (2 g3 and tetrabutylammonium bromide (0.7 g) are added to a solution of 4 g of this compound in 30~ ace~onitrile (50 ml) and the mixture is .1 ~.
1; :
..
, refluxed for 3 hours. After evaporation to dryness, the residue is partitioned between uater and ethyl acetate and the organic phase is evaporated to dryness. A solution of the residual oil (2.5 g of 3(2-~ethoxyphenoxy)-1-acetyl-mercaptopropane-2-ol in di~ethoxyeehane (50 ml) is treated uith 28% aqueous am~onium hydroxide (10 ~l~; the ~ixture is kept for 3 hours at room temperature and then it is evaporated under vacuum. The oily residue is purified by column chro~atography (silica eel - 230-400 ~esh - AcOEt) to give 1.7 g of 3-(2 methoxy-phenoxy-1-~ercaptopropan-2-ol.
Using in the procedure of exa~ple 7 a suitable 3-(aryloxysubstituted)-1,2-propane-diol of examples and 2, the follo~ing compounds are obtained~
- 3(4-~ethoxy-phenoxy)-~ercapto-propane-2-ol;
- 3(3,4,5-trimethoxy phenoxy)1-mercapto-propane-2-ol;
- 3/4-(i~idazol-1-yl)phenoxy/-1-mercapto-propane-2-ol;
- 3(4-acetamido-phenoxy)-1-~ercapto-propane-2-ol.
' EXA~PLE 9 A stirred ~ixture of 3-(2-methoxy-phenoxy)propane-1,2-diol (100 g~
sulphosalicylic acid (~ g~ and 2-bromo-ethanal, diethyl acetal is heated for 4 hours At 1OO C, distilline off ethanol. After cooling, the reaction .
'~ ~ixture is diluted ~ith e~hyl acet~te (100 ~ a6hed with 5X aqueous NaHC03 and ~ater; after dryin8 on Na2S04 the solvent is evaporated in vacuu~. The resi-due is crystallized fro~ diisopropyl ether to afford 15.4 e of , . .
(Z,E)-2-~romomethyl-(2-ethoxy-phenoxy)methyl-(1,3~-dio-xolane, ~.p. 65-53 C. A solutlon of this compound (10) , .
1 32666~
in CCl~ (25 ml) is adsorbed on a silica ~el column (400 g) and eluted with AcOet / petroleum ether (1 : :
1) to give 4 g of .' (E)-2-bromomethyl-4-(2-methoxy-phenoxy)-methyl-1,3-dio-xolane, M. p. 52-53 C and 4 g of ~Z~-2-bromomethyl-4-(2-methoxy-phenoxy)methyl- :~
1,3-dioxolane~ m~p. 60-61 C /after ~rystallization ~:
from EtOH).
EXA~PLE 10 Using in the procedure of example 9 a suitable 3-substituted 1,2-propandiol, the follo~inæ compounds are obtained: :
- (Z,E)-4-(2-hydroxy-phenoxy)methyl-~-bromo~ethyl-(1,3)-dioxolane;
(Z,E)-4-(3,4,5-trimethoxyphenoxy)methyl-2-bromomethyl-(1,3)-dioxolane;
- (Z,E)-4-(3,5-dimeehoxy-4-hydroxy-phenoxy3~ethyl-2-bromomethyl-(1,3)-dioxolane; :
tZiE)-4-(3,5-diterbutyl-4-hydroxy-phenoxy)methyl-2-bro~omethyl-~1,3)-dioxolane;
- (Z,E)-4~/4-(imida~ol-l-yl)phenoxy/-methyl-2-bromomethyl(1:,3)-dioxolane;
- (Z,E)-4-(4~acetamidophenoxy)me~hyl-2-bromomethyl-(1,3)-dioxolane;
(Z,E)-4-/2-methoxy-4-allyl-phenoxy/-methyl-2- :~
bromomethyl-(1,3)-dioxolane;
- : (Z,E)-4-~4-~ethoxyphenoxy)methyl-2-bromomethyl (1,3)-dioxolane.
EXA~PLE 1~ .
A stirred suspension of potassium acotaee (13.5 g) and . ::
of , ;: : :
; ~ (Z,E~-2-bromomethyl-4-(4-methoxy-phenoxy)methyl-1,3- .
dioxolane (20 8) in dimethylsulphoxide (100 ml) is ...
~: ` ~ "''' ,:
heated for 2 hours at 100 C. After cooling the reaction mixture is poured in iced water (250 ml) and extracted uith diethylether. After anidrification on Na2S04 and solvent remo~al, the purification of the i crude residue by column chromatography (silica gel 230-100 mesh, eluent : hexane / AcOEt = 3 : 1) yields 15 g of (Z,E)-2-acetoxymethyl-4-(4-methoxyphenoxy)-methyl- ~-;
(1,3)-dioxolane as a clear oil.
IR ~ = 1735 cm (~ C = 0), ~ =1240 cm ( C-0 as,sim) = 1100 cm (~ as C-0-C alicyclic ethers); NMR (CDCl3) ~ = 2.34 3H (s) CH3C0-A solution of this compound in dimethylsulhpoxid~ is treated ~ith a solution of potassiu0 carbonate (17 g) in uater (60 ~l) and heated for 3 hours at 50 C. The aqueous solution is saturated ~ith NaCl and extracted uith ethyl acetate. The extracts are dried, decolourized ~ith charcoal and evapor~ted to dryness under vacuum to give after trituration with diisopropylether 12 ~ of tZ,E3-2-hYdroxy~eth~l-4-(4-methoxy-phenoxy)methyl-1~3-~
dioxolaDe, m.p. 44-49 C. ~-EXA~PLE 12 A suitable 4-~substituted 2-halomethyl-(1,3)-dioxolane of examples 9 nnd 10 is reacted according to the , ~
exa~ple 11 and ~he follouing compounds are obtained:
(E)-4-t2-methoxyphenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane, m . p . 6 8 - 6 9 C;
- (Z)-4-(2-methoxyphenoxy3methyl-2-hydroxymethyl (1,3)-dioxol~ne, m.p.S7-59 C; ~
- (Z,E)-4-(4-mçthoxyphenoxy)mcthyl-2-hydroxymethyl (1,3~-dioxolane;
, ~ .
- (7"E)-4-(3,4,5-trimethoxyphenoxy)meth~l-2-hydroxymethyl-(1,3)-dioxolane;
,: .: .
1 3~6668 - (Z,E)-4-(3,5-dimethoxy-4-hydroxy-phenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane;
- (Z,E)-3-(3,5-diterbutyl-4-hydroxy-phenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane;
- (Z,E)-4-(4-acetamidophenoxy)methyl-2-h~droxymethyl (1,3)-dioxolane;
- (Z,E)-4-/(imidazol-1-yl)phenoxy/methy1-2-h~droxy~ethyl-(1,3)-dioxolane; -- (Z,E)-3-/2-methoxy-4-allyl-phenox~J-methyl (1,3)-dioxolane.
~ ':
A stirred suspension of (Z,E)-2-(2-methoxyphenox~
methyl-4--bro~omethyl-1,3-dioxolane (6.84 ~) and -~
potassiu~ thioacetate (5.08 g~ in acetonitrile (300 ~l) is refluxed for 5 hol~rs under inert gas atmosphere.
The solvent is concentrated to a small volu~e and the residual mixture is poured into iced water.
The aqueous phase is extracted uith ethyl aceate to give ater the usual wor~-up an oily residue ~hich is purified by column chromato~raphy (silica gel ; 230-600 ~esh - hexane ~ eth~l acetate = 1 : 1) so ieldi~ 3 g of (Z,E)-2-~2--methoxyphenoxy)-methyl-4-ac tylthiomethyl-~1,3)-dioxolane as a limpid oil, (IR~= ~ 16gO c0 ( ~ C
O of RCOSR) NHR (CDCl~ 2.3 3H (s) CH3-C~S-;
= 3.1-2.9 2H (d)~ CH2-S-; ~ ~ 5.2 1H (t)-~-CH-O-). ~;
A solution of 2 g of this co~pound in dimethoxyethane ~ is treated ~ith concentrated ammonium hydroxide (S ml) at room temperature, under nitrogen.
After 24 hours the reaction mixture is concentrated to -~
, ., ; dr~ness under YaCuum and the residue is diluted ~ith eth3~l acetate. The o~r~anic phase is washed with water ( 2 x 5 ml), dried on Na2S04 and concentrated to . .. - - -:
- 27 - .
dryness. The residue is purified b; column chromatography (silica ~el - 230-400 mesh - hexane / -::
ethyl acetate = 1 : 2) and 0.7 g of 2-(Z,E)-2-methoxyphenoxy)methyl- -.
4-~ercaptomethyl~(1,3)dioxolane are obtained as uncoloured oil (IR = ~ = 2250 cm , ( ~ SH) ~MR
(CDCl3)~= 3-3.15 2H dd-CHS-. -:
EXA~PLE 14 Using in the procedure of example 12 a suitable 2-halo~loethyl-dioxolane of the examples 9 and 10, the followin~ co~pounds are obtain~d:
- (Z,E)-2-acetylthiomethyl-4-(4-methoxy-phenoxy) methyl-(1,3)-dioxolane;
- (Z,E)-2-~ercaptomethyl-4-(4-~ethoxy-phenoxy)~ethyl (1~3~-dioxolane;
- (Z,E)-2-acetylthiomethyl-4-(3,4,5-trimethoxy-phenoxy) ~ethyl-(1,3)-dioxolsne.
EX~MPLE 15 I A solution of (E3-2-hydroxymethyl-4-(2-methoxyphenoxy) mPthyl-1,3~dioxolane in dimethylformamide (DMF) is adde~ under nitrogen atmosphere to a suspension of sodium hydride (80 X in mineral oil, 0.57 g). The ixt~Jre i5 uarmed at 40 C for 30', and then cooled at 0-10 C,slouly added dropuise thereto a solution of 1 ethyl bromoacetate ~2.12 ml) in DMF. After 12 hours at roo~ temperature, the reaction mixture is diluted uith aqueous NaH2P0~ (100 ~l) and: extracted with ethyl : -~:
acetate. After washing uith uater (3 ~ 30 ml) the organic phase is dried on Na2S06 and evaporated under ~ vacuum to give 2.7 g of ethYl ~: : 4-/(E)-~-~2-methoxy~phenoxy)methyl-t1 3)-": ~ ~ ' dioxolane-2-yl/-3-oxa-butanoate as a clear oil (NMR : :
~: CDCl3) i ~: , ~, : j 1 3~6668 = 1,2,3H (t) 3 2 ; 3.6,2H(~)-C~2-O-CH2COOEt, ~ =3,8,3H(s) CH3-O-,~= 5,2,lH(t)-O-CH-O;o= 6,8 4H(s) CH(aromatic).
A suspension of this compound in aqueous NaOH N t20 ~l) is stirred for 3 hours at room temperature to obtain a clear solution uhich is then extracted with ethyl acetate (2 x 10 ml) and the or8anic phase is discarded. The aqueous phase is acidified to pH 2,5-3 b~ treatment with a 10~ aqueous RHS04 solution and ex~racted ~ith ethyl acetate (5 x 10 mi). These organic extracts are collected, ~ashed ~ith water ~ 2 x 10 ml) dried on Na2S04 and concentrated to dryness under vacuum. The residue crystallizes from diisopropyl ether affording 2.0 g of 3~oxa-4-/4-(2-0ethoxy-phenoxy)methyl-(E) (1,3~-dioxolane-2-yl/butanoic acid; ~.p.B6-88 C.
In a similar ~ay and starting from (Z)-4-/(2-methoxy-phenoxy)-methyl/-2-bromo-~ethyl (1,3) dioxolane and from a (1~ ixture of the Z and E isomers, the follouing compounds are obtained ;~
respectively~
- 3-oxa-4-t4-/2-methoxypheno~y)methyl-(Z)-(1,3) dioxolan-2-yl/butanoic acid, ~.p. 64-66 C and 3-oxa-4~(2-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolan-2 yl/butanoic acid, m.p. 68-69 C.
EXAMPLE 1 é~
Using in the procedure of example 14 a suitable , :: -.
4-~ubstituted-2-bromomethyl-dioxolane of the examples ~ -9 and 10, the follouing compounds are obtained: ~
3-oxa-4-t4-~3,5-diterbutyl-4-hydroxyphenoxy)methyl .,.~' ~ tZ,E3-/1,3)-dioxolan-2-yl/-butanoic acid; ~ !~
1 - 3-oxa-4-/4-(3,5-diMethoxy-4-hydroxyphenoxy~methyl.'.
(Z,E)-(1,3j-dioxolan-2-yl/-butanoic acid;
3-oxa-4-/4-(3,4,5-triaethoxyphenoxs~)meeh (Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid ., . ,':' - 3-oxa-4/4-(2-methoxy-4-allyl-phenoxy)methyl-~Z,E)-(1,3~-dioxolan-2-yl/butanoic acid;
3-oxa-4/4-(4-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid.
EX~MPLE 17 A solution of methyl thioglycolate (1.62 ml) in methanol (5 ml~ is added dropwise under an inert gas atmosphere to a stirred solution of sodium methoxide (from 0.46 g of Na) in methanol (40 ml3; after 30 minutes 5 g o~ (Z,E)-2-bromo-methyl-4-(2-methoxy-phenoxy)methyl-1,3-dioxolane are added dropwise to the mixture.
The mixture is refluxed for 2 hours, diluted with aqueous 2N NaOH (8.5 ml~ and heated again for 2 hours at the reflux temperature.
After concentration to a small volume the mixture is diluted with water (20 ml) and washed with ethyl acetate and these extracts are discarded. The aqueous phase is then acidified to pH 2.5 (H2SO42N) and extracted with ethyl acetate (3 x 20 ml). The combined extracts are dried on Na2S04, evaporated to dryness under vacuum to yield 3.2 g of 3-thia-4-/4-(2-methoxy-phenoxy)-methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid (m.p. S2-67C) using in the same procedure, pure (Z) or (E)-2-bromomethyl-dioxolanes the following pure geometrical isomer~: 3-thia-4-/4-(2-methoxy-phenoxy)methyl-(Z)-~1,3)-dioxolan-2-yl/~utanoic acid (m.p. 82-840C) and 3-thia-4-/4-(2-methoxy- -phenoxy)methyl-(E)~(1,3)-dioxolan-2-yl/-butanoicacid(m.p.
78-82C) are obtained.
E~MP~
Using in the procedure of example 17 a suitable 4-substituted 2-halomethyl-dioxolane of the examples 9 and 10, the following compounds are obtained:
- 3-thia-4-/4-(4-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-yl/butanoic acid;
,. ..
:
`~ ~3 :.
..
- 3-thia-4-/4-(2-hydroxy-phenoxy~methyl-(Z,E)-(1,3) :~
dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(3,4,5-trimethoxy-phenoxy)methyl-(Z1) (1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(3,5-dimethoxy 4-hydroxy-phenoxy)methyl (Z,E3-(1,3)-dioxolan-2-yl/butanoic acid;
- 3-thia-4-/4-~4-imidazol-1-yl-phenoxy3methyl-(Z,E) (1,3)-dioxolane-2-yl~-butanoic acid;
- 3-thia-4-/4-(3,5-diterbutyl-4-hydroxy-phenoxy)methyl (Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-~4-(4-acetamido-phenoxy)methyl-~Z,E) (1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(2-methoxy-allyl-phenoxy)methyl-~Z,E) (1,3)-dioxolane-2-yl/butanoic acid.
Using~ N-acetyl-L-cysteine ~ethylester and -2-tS~-~ercapto-propionylglycine ethylester instead of :
: methylthio81ycolate in the procedure of exa~ple 17 and by reaction ~ith a suitable 2-halo-methyl-dioxol~ne of -~
examples 9 and 10, the followin8 compounds are :: :
o~ta~ined: ~.
2:-(~acetylamino)-4-thia-5-/4-(2 methoxy-phenoxy)methyi-(Z,E~ 3)-dloxolane-2-yl/-pentanoic acid;
, ~ ::
2-(acetylamino~-4-thia-5/4-/4~methoxy-phenoxyj~ethyl-(Z,E)-(1,3)-di~xola:ne-2-yl/-pentanoic acid;
-; (2~)-2-~ethyl-3-thia 4-/4-;(2-~ethoxy-phenoxy)methyl :~
)-(1,3)-dioxolane-2-Yl/-butanoylglycine;
(2S)-2-methyl~3-thia-4-/4-(4-methoxy-phenoxy)methyl : -(Z,E)~ ,3)-dioxol~n-2-yl/-butanoyl glycine. :
~: ,.. :
EXAMPLE 20 --:
, ~ ,':
:, . ::
-1 32666~ ~
Using in the procedure of example 9 a 3-substituted propane-l-mercapto-2-ol of example~ 7 and 8 instead of the 3-substituted propane-1,2-di~1 by reaction with 2-bromo-ethanol diethyl acetal in presence of sulfosalicylic acid, the follo~ing (1,3)-thioxolanes are obtained:
- (Z,E)-4-(2-methoxy-phenoxy)methyl-2-bromo~ethyl-(1,3)thioxolane;
- (Z,E)-4-(4-methoxy-phenoxy)methyl-2-bromomethyl (1,3)-thioxolane;
- (~,E)-4-(3,4,5-tri~ethoxy-phenoxy)methyl-2-bromomethyl-(1,3)~thioxolane; :
- (Z,E)-4-(4-imida~ol-1-yl-phenoxy)methyl-2-bromomethyl-(1,3)-thioxolane;
- (Z,E)-4-(4-acetamido-phen~xy)methyl-2-bromomethyl (1,3)-thioxolane.
By reaction of a 2-halomethyl-(1,3)-thioxolane of example 20 with ethyl thioglycolate, N-acetylcystcine ~ethylester or 2S-mercaptopriopionylglycine, according to the examples 17 and 19, the follouin~ compounds are :~
obtained:
: - 3-thia-4-/4-~2-methoxy-phenoxy)~ethyl-(~,E)-(1,3)-thioxolane-2-yl~-butanoic acid;
-3-thia-~4-/4-(4-~ethoxy-phenoxy)methyl-(1,3)-thioxolan-2-yl/-butanoic acid;
- 3-thia-4-~4-(3,4,~5-tri~ethoxy-phenoxy)~ethyl-(Z,E)-(1,3)-thioxolan-2-yl-butanoic acid;
~ - : 3-thia-4-/4-(4-imidazol-1~yl-phenoxy)methyl-(Z,E)-}~ (1,3~-thioxolan-2-yl/-butanoic acid;
~ 3-thia-4-/4-(4-acetamido-phenoxy)methyl-(Z,E~- -.i: .
(1,3)-thioxolan-2-yl/-butanoic acid; ~:
- 2-(acetylamino)-4-thia-5/4-(2-methoxy-phenoxy)-methyl-(~,E)-(1,3)-thioxolan-2-yl~-pentanoic acid;
, :
1 3~666~
- 2-acetylamino-4-thia-5-/4-~4-methoxy-phenoxy)methyl (1,3)-thioxolan-2-yl/pentanoic acid;
- (2S)-2-methyl-3 thia-4-~4-(2-methoxy-phenoxy)methyl (Z,E)-(l,3)-thioxolane-2-ylJ-b~tanoyl-glycine.
A solution of 2-(2-methoxy-phenoxy)ethanale ~48 ~) ~
3-bromo-l,2-propandiol (52,7 g) and p-toluensulphonic --acid (3.85 g) in benzene (500 ml~ is refluxed for 5 ho~rs with azeotropic removal of the water formed during the reaction.
Potassium carbonate (20 g) is added to the cooled solution, the st~spension is stirred oYernight, f f;ltered and the filtrate is evaporated to dryness in vacuum to give an oily residue which is distilled in -~
hi8h vacuum (m.~.178-185 C 0.5 mm ~g~ to obtain 33.4 g of (Z,E)-2-(2-methoxyphenoxy)methyl-4-bromomethyl-1,3~dioxolane.
Usi~g in the prooedure of example 22 a suitable 2-substituted ethanale of examples 3 and 4, the I fo~lowin~ oompounds are obtained;
(Z,E)-2 ~4-methox~-phenoxy)methyl-4-bromomethyl-~J ~ ( 1,3)-dioxolane;
; (Z,E) 2-(3,4,5-trimethoxyphenoxy)methyl 4-bromomethyl i ~ (1,3)-dioxolane;
(Z,E)-2-(4-imidazol-1-yl-phenoxy)methyl-4-bro~omethyl (1,3)-dioxolane; ;
~ ~ (Z,E)-~-/2-methoxy-4-allyl-phenoxy/methyl-4-bromomethy~
i ~ ~ (1,3)-dioxolane.
j ~ EXAMPLE 24 ~: :,,'', ~il ~ ' .
~ 32666~
By reaction of a (Z,E)-2-(2-methoxy-phenoxy)-methyl-4-bromomethyl-1,3-dioxolane of examples 22 and 23 with potassium acetate, according to the exam,ple 11, or uith potassium thioacetate, according to the example 13, or respectively ~ith methyl thioglycolate or N-acetylcysteine methylester, according to the examples 17 and 19, the following compounds are obtained:
(Z,E)-2 (2-methoxy-phenoxy)methyl-4-acetoxymethyl-dioxolane; ~;-~Z,E)-2-(2-methoxy-phenoxy)me~hyl-4-hydroxymethyl- --dioxolane;
(Z,E)-2 (2-~,ethoxy-phenoxy3methyl-4-acetylthiomethyl ~.
dioxolane; ,~
(Z,E)-2 (2-methoxy-phenoxy)~ethyl-4-mercaptomethyl dioxolane;
3~thia~4-/2-(2-methoxy-phenoxy~ethyl-(Z,E)-(1,3)-dicxo-lan-4-yl/-butanoic acid;
2-(acetylamino)-4-thia-S-~2-(2-methoxy-phenoxy)methyl (Z,E)-(1,3)-dioxolan-4-yl/-pentanoic acid (m.p. - :.
80-82'C).
j : :
j~ ~XAHPLE 25 '~:
By reaction, of a methanesulphonate of examples 5 and 6 ~ith a metl1yl thioglycolate, accordin,3 to the example ::
17, the follouing compounds are obtained: :
3-thia-5-(2-methoxy-phenoxy)-pentanoic acid, ~.p. .
69-71 C;
3-thia-5-(4-methoxy-phenoxy)pentanoic acid; ; -3-thia-5-(3,4t5-trimethoxy-phenoxy)pentanoic acid; ~ -3-thia-5-~3,5-dimetho~y~4-hydroxy-phenoxy)pentanoic acid;
3-thia-5-(4-im,ida~ol-1-yl-phenoxy~pentanoic acid;
3-thia-5-(6-acetamido-phenoxy)pentanoic acid;
3-thia-5-(2-methoxy-4-alIyl-phenoxy)-pentanoic acid.
. - ":
Methanesulphonylchloride (31.7 ml) is slo~ly added dropwise to a stirred solution of 3-p~ridylcarb inol (39.6 ml) and triethylamine (55.7 ml) in dichloroethane (600 ml), cooled at O C.
The reaction mixture is left for 40 minutes at O C and filtered. The organic filtrate is washed ~ith water (2 x 100 ml) and then it is treated with a solution of potassium thioacetate (48 g ) in uater (250 ml) for 2 hours under vigorous stirring.
The separated organic phase is uashed ~ith ~ater (2 x 100 ml), dried on Na2S04, and evaporated to dryness in vacuum to give an oily residue of crude 3-(acetylthiomethyl)pyridine (48 g).
A solution of potassium carbonate (1.4 g) in uater (5 ml) and 2-(2-methoxy-phenoxy)ethyl methane 6ulphonate (1.05 g) are added to a solution of this crude 3-(acetylthiomethyl3-pyridine (0.7 g) in ethanol (20 ml); the stirred mixture i3 heated for 2 hours at 5 0 C .
The mixture is cooled, diLuted uith water and I extracted with ethyl acetate (2 x 20 ml). The j collected or~anic extracts are uashed ~ith ~ater (3 x ! 10 ml), dried and evaporated to dryness in vacuum. The 1~ oily residue is purified by column chromatography - . .
I (silica 8el - 230 - 400 mesh - AcoEt) to give 1 g of 1-(3-pyridyl)2-thia-4-(2-methoxy-phenoxy) butane as a clear oil.
¦~ NHR (CDCl3) : ~ - 2,75,2H (t) CH2-S-; ~ = 3,B-3,85,3 ~ 2H (2s)-OCH3 + S-CH2-Py; ~ = 4,15 2H (t) -CH2-0-;
i 6,8 4H (s3phenyl; 7-8,7 4H (m)-pyridyl. -~
EXA~PLE 27 ''.:".
: B
~ ~ .
By reaction ~f a suitable halomethyl-(1,3)-dioxolane of examples 9, 10, 22 and 23 or of a s~itable halomethyl-(1,3)-thioxolane of example 20 and/or ~-suitable ~ethanesulphonates of the examples S and 6 uith a (acylthiomethyl)psridine prepared according to example 26 , the follo~in~ compounds are obtained:
(Z,E)-2-(3-pyridyl-~ethylthio~methyl-4-(2-methoxy-phenoxy3-methyl-(1,3)-dioxolane;
(Z,E)-4-(3-pyridyl-metnylthio)methyl-2-(2-methoxy-phenoxy)-methyl-(1,3)-dioxolane;
(Z,E)-2-~3-pyridyl-methylthio)methyl-4-(4-methoxy-phenoxy)~ethyl-(1,3)-dioxolane;
(Z,E)-2-~3-pyridyl methylthio3~ethyl-4-(2-methoxy-phenoxy) methyl-(1,3)-thioxolane;
1-(3-pyridyl)-2-thia-4-(4-methoxy-phenoxy)butane;
1-(3-pyridyl)-2-thia-4-(4-acetamido-phenoxy)-butane;
1-(3-pyridyl)-2-tbia-4-(4-i~idazol-1-yl-phenoxy) butane;
1 1-(3-pyridyl)-2-thia-4-/2-methoxy-4-allyl-phenoxy~ ~-i butane.
~A~PLE 28 A solution o dicyclohexylcarbodiimide t2.5 g~ in DMF
(10~ml) is slo~l~y added dropuise to a solution of 3-thia-4-/4-(2-methoxy-phenoxy)methyl-tZ,E)-(1,3)-dioxolan-2-yl/-butanoic acid ~3.14 g) snd 3~amino~ethyl-pyridine (1.08 g3 in dimethylformamide t10 ~ cooled at O C.
After 30~ at O C, the reaction temperature is raised up to room te~perature. After 4 hours the mixture is filtered and concentrated to dryness under vacuum; the ~-~i~ residue is purified on silica eel column (EtOAc / HeOH
¦` ~ - 10 : 1) affordine 2.5 s of 3-thia-6-/4-(2-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxo-lan-2-yl/-butanoic acid H-(3-pyridyl)-meth~l amide.
.j :
: !
By reacting according to example 28 the appropriate carboxylic acids with 3-aminomethyl-pyridine, the following compounds are obtained:
N-(3-pyridyl~methyl-3-thia-5-(2-methoxy-phenoxy) ~:
pentanoic acid amide;
N-(3-pyridyl)methyl-3-thia-5-(4-methoxy-phenoxy) ~ -pentanoic acid amide;
N-(3-pyridyl~methyl-3-thia-5-(3,4,5-trimethoxy-phenoxy ~ ~
pentanoic acid amide; --~-N-53-py~idyl)methyl-3-thia-4-/4-(2-methoxy-phenoxy)me- ~',':
thyl-(Z,E)-(1,3)-dioxolan-2-yl~-butanoic acid amide;
N-t3-pyridyl~methyl-3-thia-4-/4-(4-methoxy-phenoxy) :~
methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide;
N-(3-pyridyl)methyl-3-thia-4-/2-(2-methoxy-phenoxy) ~:
methyl-(W,E)-(1,3)-dioxolan-3-yl/-butanoic acid amide; -N-(3-pyridyl)methyl-3-oa-4-/4-(2-methoxyphenoxy) -~.
methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide. -:
'"':'' :
1; : ~: ' .
:
'~ .
~: :,`' 1 B:
~ .
EXA~PLE 4 Using a suitable 3-substituted-propane-1,2-diol of the ex~mple 2 in the procedure of example 3, the follouing 2-su~stituted ethanales are obtained:
- 2(2-methoxyphenoxy)etha~ale (~.p.65-67 C);
- 2~3,4,5-trimethoxypheno~y)ethanale;
- 2/4-(imida~ol-1-yl)phenoxy~-ethanale;
- 2-/2-methoxy-4-allyl-phenoxy/-ethanale.
. .:
EXA~PLE 5 Sodiu~ borohydride (3.78 g) is added to a solution of 2~2-met~oxyphæinoxyethanale (16.6 ~) in methanol (20 ml) cooled at O C, in small portions, keeping the tem-perature under 10 C. After 30' at 10 C the reaction ~ixture is poured in aqueous NaH2P04 30~ (200 ~l) and extracted with ethyl acetate ( 3 x 100 ml). The o~ganic extracts are ~ashed ~ith ~ater, dried on Na2S06 and concentrated under vacuum to give 2-(4-~ethoxy-pheno~y)ethanol-2-(4-methoxypheno~y) (13.5 ~) as a yellou oil (NMR (CDCl3) ~ = 2,8.3,7, 1H
(m) OH disappears with D20; IR: = ~ 3000-3600 cm OH).
A solution of 5~ 8 of the above product in dichloroethane (40 ml), cooled at O C, is treated ~ith triethylamine (4.6 ml) and uith a solution of methanesulphonyl chloride (2.55 ml~ in dichloroethane which is then addcd dropuise. The reaction mixture is . - ::, stirred for 3 hours at room temperature and then ~iltered.
':
-- 22 - 132~668 The filtrate is washed with water, 5~ii aqueous NaHCO3 and again with water. After anhydrification on sodium sulphate and removal of the solvent under vacuum the residue is crystallized from isopropyl ether to give 5.4 g of 2-(2-methoxyphenoxy)-ethylmethanesulphonate, m.p. 73-76CO
After reduction of a suitable 2-substituted ethanale of the sxamples 3 and 4 with NaBH4 and after reaction with methane sulphonyl chloride, according to example 5, the following methanesulphonates are obtained:
- 2-/2-methoxy-4-allyl-phenoxy/-ethyl methanesulphonate;
- 2(4-methoxyphenoxy)ethyl methanesulphonate;
- 2-(4-imidazol-1-yl-phenoxy)ethyl methanesulphonate;
- 2-(4-acetamidophenoxy)ethyl methanesulphonate.
~XaMPLE 7 A solution of 3-(2-methoxy-phenoxy)-propane-1,2-diol (4.7 g) in pyridine, cooled at 5-10C, is treated under stirring with a solution o p-toluensulphonylchloride (4.5 g) in benzene (70 ml). The reaction mixture is stirred overnight at room temperature, then it i5 washed with 2N HCl (3 x 100 ml3 and with waterl dried on Na2SO4 and evaporated to drynesiqi in vacuum. The oily residue is purified by column chromatography (silica gel - 230-400 mesh hexane/ AcOEt =
3J1) to yield 5 y of 3-(2-methoxy-phenoxy)-2-hydroxy-1-propyl p-toluensulphonate (oil, NMR (-CDc13): = 2,4 3H (s) CH3SO2; = 3,75-4,4 5H (m) OCH3 + OCH2).
Potassium thioacetate (2 g3 and tetrabutylammonium bromide (0.7 g) are added to a solution of 4 g of this compound in 30~ ace~onitrile (50 ml) and the mixture is .1 ~.
1; :
..
, refluxed for 3 hours. After evaporation to dryness, the residue is partitioned between uater and ethyl acetate and the organic phase is evaporated to dryness. A solution of the residual oil (2.5 g of 3(2-~ethoxyphenoxy)-1-acetyl-mercaptopropane-2-ol in di~ethoxyeehane (50 ml) is treated uith 28% aqueous am~onium hydroxide (10 ~l~; the ~ixture is kept for 3 hours at room temperature and then it is evaporated under vacuum. The oily residue is purified by column chro~atography (silica eel - 230-400 ~esh - AcOEt) to give 1.7 g of 3-(2 methoxy-phenoxy-1-~ercaptopropan-2-ol.
Using in the procedure of exa~ple 7 a suitable 3-(aryloxysubstituted)-1,2-propane-diol of examples and 2, the follo~ing compounds are obtained~
- 3(4-~ethoxy-phenoxy)-~ercapto-propane-2-ol;
- 3(3,4,5-trimethoxy phenoxy)1-mercapto-propane-2-ol;
- 3/4-(i~idazol-1-yl)phenoxy/-1-mercapto-propane-2-ol;
- 3(4-acetamido-phenoxy)-1-~ercapto-propane-2-ol.
' EXA~PLE 9 A stirred ~ixture of 3-(2-methoxy-phenoxy)propane-1,2-diol (100 g~
sulphosalicylic acid (~ g~ and 2-bromo-ethanal, diethyl acetal is heated for 4 hours At 1OO C, distilline off ethanol. After cooling, the reaction .
'~ ~ixture is diluted ~ith e~hyl acet~te (100 ~ a6hed with 5X aqueous NaHC03 and ~ater; after dryin8 on Na2S04 the solvent is evaporated in vacuu~. The resi-due is crystallized fro~ diisopropyl ether to afford 15.4 e of , . .
(Z,E)-2-~romomethyl-(2-ethoxy-phenoxy)methyl-(1,3~-dio-xolane, ~.p. 65-53 C. A solutlon of this compound (10) , .
1 32666~
in CCl~ (25 ml) is adsorbed on a silica ~el column (400 g) and eluted with AcOet / petroleum ether (1 : :
1) to give 4 g of .' (E)-2-bromomethyl-4-(2-methoxy-phenoxy)-methyl-1,3-dio-xolane, M. p. 52-53 C and 4 g of ~Z~-2-bromomethyl-4-(2-methoxy-phenoxy)methyl- :~
1,3-dioxolane~ m~p. 60-61 C /after ~rystallization ~:
from EtOH).
EXA~PLE 10 Using in the procedure of example 9 a suitable 3-substituted 1,2-propandiol, the follo~inæ compounds are obtained: :
- (Z,E)-4-(2-hydroxy-phenoxy)methyl-~-bromo~ethyl-(1,3)-dioxolane;
(Z,E)-4-(3,4,5-trimethoxyphenoxy)methyl-2-bromomethyl-(1,3)-dioxolane;
- (Z,E)-4-(3,5-dimeehoxy-4-hydroxy-phenoxy3~ethyl-2-bromomethyl-(1,3)-dioxolane; :
tZiE)-4-(3,5-diterbutyl-4-hydroxy-phenoxy)methyl-2-bro~omethyl-~1,3)-dioxolane;
- (Z,E)-4~/4-(imida~ol-l-yl)phenoxy/-methyl-2-bromomethyl(1:,3)-dioxolane;
- (Z,E)-4-(4~acetamidophenoxy)me~hyl-2-bromomethyl-(1,3)-dioxolane;
(Z,E)-4-/2-methoxy-4-allyl-phenoxy/-methyl-2- :~
bromomethyl-(1,3)-dioxolane;
- : (Z,E)-4-~4-~ethoxyphenoxy)methyl-2-bromomethyl (1,3)-dioxolane.
EXA~PLE 1~ .
A stirred suspension of potassium acotaee (13.5 g) and . ::
of , ;: : :
; ~ (Z,E~-2-bromomethyl-4-(4-methoxy-phenoxy)methyl-1,3- .
dioxolane (20 8) in dimethylsulphoxide (100 ml) is ...
~: ` ~ "''' ,:
heated for 2 hours at 100 C. After cooling the reaction mixture is poured in iced water (250 ml) and extracted uith diethylether. After anidrification on Na2S04 and solvent remo~al, the purification of the i crude residue by column chromatography (silica gel 230-100 mesh, eluent : hexane / AcOEt = 3 : 1) yields 15 g of (Z,E)-2-acetoxymethyl-4-(4-methoxyphenoxy)-methyl- ~-;
(1,3)-dioxolane as a clear oil.
IR ~ = 1735 cm (~ C = 0), ~ =1240 cm ( C-0 as,sim) = 1100 cm (~ as C-0-C alicyclic ethers); NMR (CDCl3) ~ = 2.34 3H (s) CH3C0-A solution of this compound in dimethylsulhpoxid~ is treated ~ith a solution of potassiu0 carbonate (17 g) in uater (60 ~l) and heated for 3 hours at 50 C. The aqueous solution is saturated ~ith NaCl and extracted uith ethyl acetate. The extracts are dried, decolourized ~ith charcoal and evapor~ted to dryness under vacuum to give after trituration with diisopropylether 12 ~ of tZ,E3-2-hYdroxy~eth~l-4-(4-methoxy-phenoxy)methyl-1~3-~
dioxolaDe, m.p. 44-49 C. ~-EXA~PLE 12 A suitable 4-~substituted 2-halomethyl-(1,3)-dioxolane of examples 9 nnd 10 is reacted according to the , ~
exa~ple 11 and ~he follouing compounds are obtained:
(E)-4-t2-methoxyphenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane, m . p . 6 8 - 6 9 C;
- (Z)-4-(2-methoxyphenoxy3methyl-2-hydroxymethyl (1,3)-dioxol~ne, m.p.S7-59 C; ~
- (Z,E)-4-(4-mçthoxyphenoxy)mcthyl-2-hydroxymethyl (1,3~-dioxolane;
, ~ .
- (7"E)-4-(3,4,5-trimethoxyphenoxy)meth~l-2-hydroxymethyl-(1,3)-dioxolane;
,: .: .
1 3~6668 - (Z,E)-4-(3,5-dimethoxy-4-hydroxy-phenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane;
- (Z,E)-3-(3,5-diterbutyl-4-hydroxy-phenoxy)methyl-2-hydroxymethyl-(1,3)-dioxolane;
- (Z,E)-4-(4-acetamidophenoxy)methyl-2-h~droxymethyl (1,3)-dioxolane;
- (Z,E)-4-/(imidazol-1-yl)phenoxy/methy1-2-h~droxy~ethyl-(1,3)-dioxolane; -- (Z,E)-3-/2-methoxy-4-allyl-phenox~J-methyl (1,3)-dioxolane.
~ ':
A stirred suspension of (Z,E)-2-(2-methoxyphenox~
methyl-4--bro~omethyl-1,3-dioxolane (6.84 ~) and -~
potassiu~ thioacetate (5.08 g~ in acetonitrile (300 ~l) is refluxed for 5 hol~rs under inert gas atmosphere.
The solvent is concentrated to a small volu~e and the residual mixture is poured into iced water.
The aqueous phase is extracted uith ethyl aceate to give ater the usual wor~-up an oily residue ~hich is purified by column chromato~raphy (silica gel ; 230-600 ~esh - hexane ~ eth~l acetate = 1 : 1) so ieldi~ 3 g of (Z,E)-2-~2--methoxyphenoxy)-methyl-4-ac tylthiomethyl-~1,3)-dioxolane as a limpid oil, (IR~= ~ 16gO c0 ( ~ C
O of RCOSR) NHR (CDCl~ 2.3 3H (s) CH3-C~S-;
= 3.1-2.9 2H (d)~ CH2-S-; ~ ~ 5.2 1H (t)-~-CH-O-). ~;
A solution of 2 g of this co~pound in dimethoxyethane ~ is treated ~ith concentrated ammonium hydroxide (S ml) at room temperature, under nitrogen.
After 24 hours the reaction mixture is concentrated to -~
, ., ; dr~ness under YaCuum and the residue is diluted ~ith eth3~l acetate. The o~r~anic phase is washed with water ( 2 x 5 ml), dried on Na2S04 and concentrated to . .. - - -:
- 27 - .
dryness. The residue is purified b; column chromatography (silica ~el - 230-400 mesh - hexane / -::
ethyl acetate = 1 : 2) and 0.7 g of 2-(Z,E)-2-methoxyphenoxy)methyl- -.
4-~ercaptomethyl~(1,3)dioxolane are obtained as uncoloured oil (IR = ~ = 2250 cm , ( ~ SH) ~MR
(CDCl3)~= 3-3.15 2H dd-CHS-. -:
EXA~PLE 14 Using in the procedure of example 12 a suitable 2-halo~loethyl-dioxolane of the examples 9 and 10, the followin~ co~pounds are obtain~d:
- (Z,E)-2-acetylthiomethyl-4-(4-methoxy-phenoxy) methyl-(1,3)-dioxolane;
- (Z,E)-2-~ercaptomethyl-4-(4-~ethoxy-phenoxy)~ethyl (1~3~-dioxolane;
- (Z,E)-2-acetylthiomethyl-4-(3,4,5-trimethoxy-phenoxy) ~ethyl-(1,3)-dioxolsne.
EX~MPLE 15 I A solution of (E3-2-hydroxymethyl-4-(2-methoxyphenoxy) mPthyl-1,3~dioxolane in dimethylformamide (DMF) is adde~ under nitrogen atmosphere to a suspension of sodium hydride (80 X in mineral oil, 0.57 g). The ixt~Jre i5 uarmed at 40 C for 30', and then cooled at 0-10 C,slouly added dropuise thereto a solution of 1 ethyl bromoacetate ~2.12 ml) in DMF. After 12 hours at roo~ temperature, the reaction mixture is diluted uith aqueous NaH2P0~ (100 ~l) and: extracted with ethyl : -~:
acetate. After washing uith uater (3 ~ 30 ml) the organic phase is dried on Na2S06 and evaporated under ~ vacuum to give 2.7 g of ethYl ~: : 4-/(E)-~-~2-methoxy~phenoxy)methyl-t1 3)-": ~ ~ ' dioxolane-2-yl/-3-oxa-butanoate as a clear oil (NMR : :
~: CDCl3) i ~: , ~, : j 1 3~6668 = 1,2,3H (t) 3 2 ; 3.6,2H(~)-C~2-O-CH2COOEt, ~ =3,8,3H(s) CH3-O-,~= 5,2,lH(t)-O-CH-O;o= 6,8 4H(s) CH(aromatic).
A suspension of this compound in aqueous NaOH N t20 ~l) is stirred for 3 hours at room temperature to obtain a clear solution uhich is then extracted with ethyl acetate (2 x 10 ml) and the or8anic phase is discarded. The aqueous phase is acidified to pH 2,5-3 b~ treatment with a 10~ aqueous RHS04 solution and ex~racted ~ith ethyl acetate (5 x 10 mi). These organic extracts are collected, ~ashed ~ith water ~ 2 x 10 ml) dried on Na2S04 and concentrated to dryness under vacuum. The residue crystallizes from diisopropyl ether affording 2.0 g of 3~oxa-4-/4-(2-0ethoxy-phenoxy)methyl-(E) (1,3~-dioxolane-2-yl/butanoic acid; ~.p.B6-88 C.
In a similar ~ay and starting from (Z)-4-/(2-methoxy-phenoxy)-methyl/-2-bromo-~ethyl (1,3) dioxolane and from a (1~ ixture of the Z and E isomers, the follouing compounds are obtained ;~
respectively~
- 3-oxa-4-t4-/2-methoxypheno~y)methyl-(Z)-(1,3) dioxolan-2-yl/butanoic acid, ~.p. 64-66 C and 3-oxa-4~(2-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxolan-2 yl/butanoic acid, m.p. 68-69 C.
EXAMPLE 1 é~
Using in the procedure of example 14 a suitable , :: -.
4-~ubstituted-2-bromomethyl-dioxolane of the examples ~ -9 and 10, the follouing compounds are obtained: ~
3-oxa-4-t4-~3,5-diterbutyl-4-hydroxyphenoxy)methyl .,.~' ~ tZ,E3-/1,3)-dioxolan-2-yl/-butanoic acid; ~ !~
1 - 3-oxa-4-/4-(3,5-diMethoxy-4-hydroxyphenoxy~methyl.'.
(Z,E)-(1,3j-dioxolan-2-yl/-butanoic acid;
3-oxa-4-/4-(3,4,5-triaethoxyphenoxs~)meeh (Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid ., . ,':' - 3-oxa-4/4-(2-methoxy-4-allyl-phenoxy)methyl-~Z,E)-(1,3~-dioxolan-2-yl/butanoic acid;
3-oxa-4/4-(4-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid.
EX~MPLE 17 A solution of methyl thioglycolate (1.62 ml) in methanol (5 ml~ is added dropwise under an inert gas atmosphere to a stirred solution of sodium methoxide (from 0.46 g of Na) in methanol (40 ml3; after 30 minutes 5 g o~ (Z,E)-2-bromo-methyl-4-(2-methoxy-phenoxy)methyl-1,3-dioxolane are added dropwise to the mixture.
The mixture is refluxed for 2 hours, diluted with aqueous 2N NaOH (8.5 ml~ and heated again for 2 hours at the reflux temperature.
After concentration to a small volume the mixture is diluted with water (20 ml) and washed with ethyl acetate and these extracts are discarded. The aqueous phase is then acidified to pH 2.5 (H2SO42N) and extracted with ethyl acetate (3 x 20 ml). The combined extracts are dried on Na2S04, evaporated to dryness under vacuum to yield 3.2 g of 3-thia-4-/4-(2-methoxy-phenoxy)-methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid (m.p. S2-67C) using in the same procedure, pure (Z) or (E)-2-bromomethyl-dioxolanes the following pure geometrical isomer~: 3-thia-4-/4-(2-methoxy-phenoxy)methyl-(Z)-~1,3)-dioxolan-2-yl/~utanoic acid (m.p. 82-840C) and 3-thia-4-/4-(2-methoxy- -phenoxy)methyl-(E)~(1,3)-dioxolan-2-yl/-butanoicacid(m.p.
78-82C) are obtained.
E~MP~
Using in the procedure of example 17 a suitable 4-substituted 2-halomethyl-dioxolane of the examples 9 and 10, the following compounds are obtained:
- 3-thia-4-/4-(4-methoxy-phenoxy)methyl-(Z,E)-(1,3)-dioxolane-2-yl/butanoic acid;
,. ..
:
`~ ~3 :.
..
- 3-thia-4-/4-(2-hydroxy-phenoxy~methyl-(Z,E)-(1,3) :~
dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(3,4,5-trimethoxy-phenoxy)methyl-(Z1) (1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(3,5-dimethoxy 4-hydroxy-phenoxy)methyl (Z,E3-(1,3)-dioxolan-2-yl/butanoic acid;
- 3-thia-4-/4-~4-imidazol-1-yl-phenoxy3methyl-(Z,E) (1,3)-dioxolane-2-yl~-butanoic acid;
- 3-thia-4-/4-(3,5-diterbutyl-4-hydroxy-phenoxy)methyl (Z,E)-(1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-~4-(4-acetamido-phenoxy)methyl-~Z,E) (1,3)-dioxolane-2-yl/-butanoic acid;
- 3-thia-4-/4-(2-methoxy-allyl-phenoxy)methyl-~Z,E) (1,3)-dioxolane-2-yl/butanoic acid.
Using~ N-acetyl-L-cysteine ~ethylester and -2-tS~-~ercapto-propionylglycine ethylester instead of :
: methylthio81ycolate in the procedure of exa~ple 17 and by reaction ~ith a suitable 2-halo-methyl-dioxol~ne of -~
examples 9 and 10, the followin8 compounds are :: :
o~ta~ined: ~.
2:-(~acetylamino)-4-thia-5-/4-(2 methoxy-phenoxy)methyi-(Z,E~ 3)-dloxolane-2-yl/-pentanoic acid;
, ~ ::
2-(acetylamino~-4-thia-5/4-/4~methoxy-phenoxyj~ethyl-(Z,E)-(1,3)-di~xola:ne-2-yl/-pentanoic acid;
-; (2~)-2-~ethyl-3-thia 4-/4-;(2-~ethoxy-phenoxy)methyl :~
)-(1,3)-dioxolane-2-Yl/-butanoylglycine;
(2S)-2-methyl~3-thia-4-/4-(4-methoxy-phenoxy)methyl : -(Z,E)~ ,3)-dioxol~n-2-yl/-butanoyl glycine. :
~: ,.. :
EXAMPLE 20 --:
, ~ ,':
:, . ::
-1 32666~ ~
Using in the procedure of example 9 a 3-substituted propane-l-mercapto-2-ol of example~ 7 and 8 instead of the 3-substituted propane-1,2-di~1 by reaction with 2-bromo-ethanol diethyl acetal in presence of sulfosalicylic acid, the follo~ing (1,3)-thioxolanes are obtained:
- (Z,E)-4-(2-methoxy-phenoxy)methyl-2-bromo~ethyl-(1,3)thioxolane;
- (Z,E)-4-(4-methoxy-phenoxy)methyl-2-bromomethyl (1,3)-thioxolane;
- (~,E)-4-(3,4,5-tri~ethoxy-phenoxy)methyl-2-bromomethyl-(1,3)~thioxolane; :
- (Z,E)-4-(4-imida~ol-1-yl-phenoxy)methyl-2-bromomethyl-(1,3)-thioxolane;
- (Z,E)-4-(4-acetamido-phen~xy)methyl-2-bromomethyl (1,3)-thioxolane.
By reaction of a 2-halomethyl-(1,3)-thioxolane of example 20 with ethyl thioglycolate, N-acetylcystcine ~ethylester or 2S-mercaptopriopionylglycine, according to the examples 17 and 19, the follouin~ compounds are :~
obtained:
: - 3-thia-4-/4-~2-methoxy-phenoxy)~ethyl-(~,E)-(1,3)-thioxolane-2-yl~-butanoic acid;
-3-thia-~4-/4-(4-~ethoxy-phenoxy)methyl-(1,3)-thioxolan-2-yl/-butanoic acid;
- 3-thia-4-~4-(3,4,~5-tri~ethoxy-phenoxy)~ethyl-(Z,E)-(1,3)-thioxolan-2-yl-butanoic acid;
~ - : 3-thia-4-/4-(4-imidazol-1~yl-phenoxy)methyl-(Z,E)-}~ (1,3~-thioxolan-2-yl/-butanoic acid;
~ 3-thia-4-/4-(4-acetamido-phenoxy)methyl-(Z,E~- -.i: .
(1,3)-thioxolan-2-yl/-butanoic acid; ~:
- 2-(acetylamino)-4-thia-5/4-(2-methoxy-phenoxy)-methyl-(~,E)-(1,3)-thioxolan-2-yl~-pentanoic acid;
, :
1 3~666~
- 2-acetylamino-4-thia-5-/4-~4-methoxy-phenoxy)methyl (1,3)-thioxolan-2-yl/pentanoic acid;
- (2S)-2-methyl-3 thia-4-~4-(2-methoxy-phenoxy)methyl (Z,E)-(l,3)-thioxolane-2-ylJ-b~tanoyl-glycine.
A solution of 2-(2-methoxy-phenoxy)ethanale ~48 ~) ~
3-bromo-l,2-propandiol (52,7 g) and p-toluensulphonic --acid (3.85 g) in benzene (500 ml~ is refluxed for 5 ho~rs with azeotropic removal of the water formed during the reaction.
Potassium carbonate (20 g) is added to the cooled solution, the st~spension is stirred oYernight, f f;ltered and the filtrate is evaporated to dryness in vacuum to give an oily residue which is distilled in -~
hi8h vacuum (m.~.178-185 C 0.5 mm ~g~ to obtain 33.4 g of (Z,E)-2-(2-methoxyphenoxy)methyl-4-bromomethyl-1,3~dioxolane.
Usi~g in the prooedure of example 22 a suitable 2-substituted ethanale of examples 3 and 4, the I fo~lowin~ oompounds are obtained;
(Z,E)-2 ~4-methox~-phenoxy)methyl-4-bromomethyl-~J ~ ( 1,3)-dioxolane;
; (Z,E) 2-(3,4,5-trimethoxyphenoxy)methyl 4-bromomethyl i ~ (1,3)-dioxolane;
(Z,E)-2-(4-imidazol-1-yl-phenoxy)methyl-4-bro~omethyl (1,3)-dioxolane; ;
~ ~ (Z,E)-~-/2-methoxy-4-allyl-phenoxy/methyl-4-bromomethy~
i ~ ~ (1,3)-dioxolane.
j ~ EXAMPLE 24 ~: :,,'', ~il ~ ' .
~ 32666~
By reaction of a (Z,E)-2-(2-methoxy-phenoxy)-methyl-4-bromomethyl-1,3-dioxolane of examples 22 and 23 with potassium acetate, according to the exam,ple 11, or uith potassium thioacetate, according to the example 13, or respectively ~ith methyl thioglycolate or N-acetylcysteine methylester, according to the examples 17 and 19, the following compounds are obtained:
(Z,E)-2 (2-methoxy-phenoxy)methyl-4-acetoxymethyl-dioxolane; ~;-~Z,E)-2-(2-methoxy-phenoxy)me~hyl-4-hydroxymethyl- --dioxolane;
(Z,E)-2 (2-~,ethoxy-phenoxy3methyl-4-acetylthiomethyl ~.
dioxolane; ,~
(Z,E)-2 (2-methoxy-phenoxy)~ethyl-4-mercaptomethyl dioxolane;
3~thia~4-/2-(2-methoxy-phenoxy~ethyl-(Z,E)-(1,3)-dicxo-lan-4-yl/-butanoic acid;
2-(acetylamino)-4-thia-S-~2-(2-methoxy-phenoxy)methyl (Z,E)-(1,3)-dioxolan-4-yl/-pentanoic acid (m.p. - :.
80-82'C).
j : :
j~ ~XAHPLE 25 '~:
By reaction, of a methanesulphonate of examples 5 and 6 ~ith a metl1yl thioglycolate, accordin,3 to the example ::
17, the follouing compounds are obtained: :
3-thia-5-(2-methoxy-phenoxy)-pentanoic acid, ~.p. .
69-71 C;
3-thia-5-(4-methoxy-phenoxy)pentanoic acid; ; -3-thia-5-(3,4t5-trimethoxy-phenoxy)pentanoic acid; ~ -3-thia-5-~3,5-dimetho~y~4-hydroxy-phenoxy)pentanoic acid;
3-thia-5-(4-im,ida~ol-1-yl-phenoxy~pentanoic acid;
3-thia-5-(6-acetamido-phenoxy)pentanoic acid;
3-thia-5-(2-methoxy-4-alIyl-phenoxy)-pentanoic acid.
. - ":
Methanesulphonylchloride (31.7 ml) is slo~ly added dropwise to a stirred solution of 3-p~ridylcarb inol (39.6 ml) and triethylamine (55.7 ml) in dichloroethane (600 ml), cooled at O C.
The reaction mixture is left for 40 minutes at O C and filtered. The organic filtrate is washed ~ith water (2 x 100 ml) and then it is treated with a solution of potassium thioacetate (48 g ) in uater (250 ml) for 2 hours under vigorous stirring.
The separated organic phase is uashed ~ith ~ater (2 x 100 ml), dried on Na2S04, and evaporated to dryness in vacuum to give an oily residue of crude 3-(acetylthiomethyl)pyridine (48 g).
A solution of potassium carbonate (1.4 g) in uater (5 ml) and 2-(2-methoxy-phenoxy)ethyl methane 6ulphonate (1.05 g) are added to a solution of this crude 3-(acetylthiomethyl3-pyridine (0.7 g) in ethanol (20 ml); the stirred mixture i3 heated for 2 hours at 5 0 C .
The mixture is cooled, diLuted uith water and I extracted with ethyl acetate (2 x 20 ml). The j collected or~anic extracts are uashed ~ith ~ater (3 x ! 10 ml), dried and evaporated to dryness in vacuum. The 1~ oily residue is purified by column chromatography - . .
I (silica 8el - 230 - 400 mesh - AcoEt) to give 1 g of 1-(3-pyridyl)2-thia-4-(2-methoxy-phenoxy) butane as a clear oil.
¦~ NHR (CDCl3) : ~ - 2,75,2H (t) CH2-S-; ~ = 3,B-3,85,3 ~ 2H (2s)-OCH3 + S-CH2-Py; ~ = 4,15 2H (t) -CH2-0-;
i 6,8 4H (s3phenyl; 7-8,7 4H (m)-pyridyl. -~
EXA~PLE 27 ''.:".
: B
~ ~ .
By reaction ~f a suitable halomethyl-(1,3)-dioxolane of examples 9, 10, 22 and 23 or of a s~itable halomethyl-(1,3)-thioxolane of example 20 and/or ~-suitable ~ethanesulphonates of the examples S and 6 uith a (acylthiomethyl)psridine prepared according to example 26 , the follo~in~ compounds are obtained:
(Z,E)-2-(3-pyridyl-~ethylthio~methyl-4-(2-methoxy-phenoxy3-methyl-(1,3)-dioxolane;
(Z,E)-4-(3-pyridyl-metnylthio)methyl-2-(2-methoxy-phenoxy)-methyl-(1,3)-dioxolane;
(Z,E)-2-~3-pyridyl-methylthio)methyl-4-(4-methoxy-phenoxy)~ethyl-(1,3)-dioxolane;
(Z,E)-2-~3-pyridyl methylthio3~ethyl-4-(2-methoxy-phenoxy) methyl-(1,3)-thioxolane;
1-(3-pyridyl)-2-thia-4-(4-methoxy-phenoxy)butane;
1-(3-pyridyl)-2-thia-4-(4-acetamido-phenoxy)-butane;
1-(3-pyridyl)-2-tbia-4-(4-i~idazol-1-yl-phenoxy) butane;
1 1-(3-pyridyl)-2-thia-4-/2-methoxy-4-allyl-phenoxy~ ~-i butane.
~A~PLE 28 A solution o dicyclohexylcarbodiimide t2.5 g~ in DMF
(10~ml) is slo~l~y added dropuise to a solution of 3-thia-4-/4-(2-methoxy-phenoxy)methyl-tZ,E)-(1,3)-dioxolan-2-yl/-butanoic acid ~3.14 g) snd 3~amino~ethyl-pyridine (1.08 g3 in dimethylformamide t10 ~ cooled at O C.
After 30~ at O C, the reaction temperature is raised up to room te~perature. After 4 hours the mixture is filtered and concentrated to dryness under vacuum; the ~-~i~ residue is purified on silica eel column (EtOAc / HeOH
¦` ~ - 10 : 1) affordine 2.5 s of 3-thia-6-/4-(2-methoxyphenoxy)methyl-(Z,E)-(1,3)-dioxo-lan-2-yl/-butanoic acid H-(3-pyridyl)-meth~l amide.
.j :
: !
By reacting according to example 28 the appropriate carboxylic acids with 3-aminomethyl-pyridine, the following compounds are obtained:
N-(3-pyridyl~methyl-3-thia-5-(2-methoxy-phenoxy) ~:
pentanoic acid amide;
N-(3-pyridyl)methyl-3-thia-5-(4-methoxy-phenoxy) ~ -pentanoic acid amide;
N-(3-pyridyl~methyl-3-thia-5-(3,4,5-trimethoxy-phenoxy ~ ~
pentanoic acid amide; --~-N-53-py~idyl)methyl-3-thia-4-/4-(2-methoxy-phenoxy)me- ~',':
thyl-(Z,E)-(1,3)-dioxolan-2-yl~-butanoic acid amide;
N-t3-pyridyl~methyl-3-thia-4-/4-(4-methoxy-phenoxy) :~
methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide;
N-(3-pyridyl)methyl-3-thia-4-/2-(2-methoxy-phenoxy) ~:
methyl-(W,E)-(1,3)-dioxolan-3-yl/-butanoic acid amide; -N-(3-pyridyl)methyl-3-oa-4-/4-(2-methoxyphenoxy) -~.
methyl-(Z,E)-(1,3)-dioxolan-2-yl/-butanoic acid amide. -:
'"':'' :
1; : ~: ' .
:
'~ .
~: :,`' 1 B:
~ .
Claims (11)
1. Compounds of formula I
(I) wherein:
Ar is phenyl;
R1, R2 and R3 are substituents of the phenyl group Ar in 2-, 3-, 4- and 5-position and which can be the same or different and are selected from the group consisting of hydrogen, hydroxy, (C1-C5)-acyloxy, (C1-C4)-alkyl, (C1-C4)-alkoxyl, (C2-C4)-alkenyl, halogen, (C1-C5)-acylamino, phenyl, phenoxy, imidazol-1-yl, carboxyl, (C1-C3)-alkoxycarbonyl, carboxy-(C1 -C4)-alkyl;
B is a valency bond, a -(CH2O-CH2)n group, 1,3-dioxolan-diyl or 1,3-thioxolan-diyl radical, X is sulphur or oxygen;
R represents a -(CH2)n, -CH(R4)-, a CH2-CH(NH2)- or -CH2-CH(NH-CORa)-group;
T is 2-, 3- or 4-pyridyl, carboxyl, -CO2R6, -COR6, -CO2NH2, -CONRdRe, -CO-NH-CH(Rc)-CO2Ra or a di-(C1-C4)-alkylamino-(C1-C4)-alkyl-aminocarbonyl, hydroxy-(C1-C4)-alkoxy-(C1-C4)-alkyl-aminocarbonyl, di-(C1-C4)-alkyl-amino-(C1-C4)-alkoxy-(C1-C4)-alkyl-amino-carbonyl or 2-, 3-, 4-pyridylmethyl-aminocarbonyl group;
n is 1 or 2;
R4 represents a (C1-C4)-alkyl or a (C2-C4)-alkenyl group;
R6 is a (C1-C6)-alkyl group optionally substituted by (C1-C6)-alkoxyl, carboxyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, morpholin-N-yl, piperidin-1-yl, 4-(C1-C4)-alkyl-piperazin-1-yl, (C3-C6)-alkenyl phenyl or phenyl-(C1-C6)-alkyl groups;
Ra is hydrogen or a (C1-C4)-alkyl group and Rc is hydrogen or a (C1-C6)-alkyl, or (C6-C14)-ar-(C1-C4)-alkyl, or heteroalkyl group of residue of a natural .alpha.-aminoacid;
Rd and Re, which can be the same or different, are hydrogen, a (C1-C6)-alkyl group, optionally substituted by a (C1-C6)-alkoxy, morpholin-n-yl, piperidin-1-yl, 4-(C1-C4)-alkyl-piperazin-1-yl hydroxy, -(C1-C4)-alkoxy-(C1-C4)-alkyl or di-(C1-C4)-alkyl-amino-(C1-C4)-alkoxy-(C1-C4)-alkyl group, or Rd and Re together with the nitrogen atom to which they are bonded form a heterocyclic ring selected from the group consisting of morpholin-N-yl, piperidin-1-yl and 4-(C1-C4)-alkyl-piperazin-1-yl, as well as their enantiomers or diastereomers and the pharmacologically acceptable salts thereof.
(I) wherein:
Ar is phenyl;
R1, R2 and R3 are substituents of the phenyl group Ar in 2-, 3-, 4- and 5-position and which can be the same or different and are selected from the group consisting of hydrogen, hydroxy, (C1-C5)-acyloxy, (C1-C4)-alkyl, (C1-C4)-alkoxyl, (C2-C4)-alkenyl, halogen, (C1-C5)-acylamino, phenyl, phenoxy, imidazol-1-yl, carboxyl, (C1-C3)-alkoxycarbonyl, carboxy-(C1 -C4)-alkyl;
B is a valency bond, a -(CH2O-CH2)n group, 1,3-dioxolan-diyl or 1,3-thioxolan-diyl radical, X is sulphur or oxygen;
R represents a -(CH2)n, -CH(R4)-, a CH2-CH(NH2)- or -CH2-CH(NH-CORa)-group;
T is 2-, 3- or 4-pyridyl, carboxyl, -CO2R6, -COR6, -CO2NH2, -CONRdRe, -CO-NH-CH(Rc)-CO2Ra or a di-(C1-C4)-alkylamino-(C1-C4)-alkyl-aminocarbonyl, hydroxy-(C1-C4)-alkoxy-(C1-C4)-alkyl-aminocarbonyl, di-(C1-C4)-alkyl-amino-(C1-C4)-alkoxy-(C1-C4)-alkyl-amino-carbonyl or 2-, 3-, 4-pyridylmethyl-aminocarbonyl group;
n is 1 or 2;
R4 represents a (C1-C4)-alkyl or a (C2-C4)-alkenyl group;
R6 is a (C1-C6)-alkyl group optionally substituted by (C1-C6)-alkoxyl, carboxyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, morpholin-N-yl, piperidin-1-yl, 4-(C1-C4)-alkyl-piperazin-1-yl, (C3-C6)-alkenyl phenyl or phenyl-(C1-C6)-alkyl groups;
Ra is hydrogen or a (C1-C4)-alkyl group and Rc is hydrogen or a (C1-C6)-alkyl, or (C6-C14)-ar-(C1-C4)-alkyl, or heteroalkyl group of residue of a natural .alpha.-aminoacid;
Rd and Re, which can be the same or different, are hydrogen, a (C1-C6)-alkyl group, optionally substituted by a (C1-C6)-alkoxy, morpholin-n-yl, piperidin-1-yl, 4-(C1-C4)-alkyl-piperazin-1-yl hydroxy, -(C1-C4)-alkoxy-(C1-C4)-alkyl or di-(C1-C4)-alkyl-amino-(C1-C4)-alkoxy-(C1-C4)-alkyl group, or Rd and Re together with the nitrogen atom to which they are bonded form a heterocyclic ring selected from the group consisting of morpholin-N-yl, piperidin-1-yl and 4-(C1-C4)-alkyl-piperazin-1-yl, as well as their enantiomers or diastereomers and the pharmacologically acceptable salts thereof.
2. Compounds according to claim 1, wherein X is oxygen.
3. Compounds according to claim 1, wherein X is sulphur.
4. Compounds according to claim 1, wherein B is a valency bond or a group (CH2-OCH2)n; with n = 1 or 2.
5. Compounds according to claim 1, wherein B is a 1,3-dioxolan-2,4-diyl, 1,3-dioxolan-4,2-diyl, 1,3-thioxolan-2,4-diyl or 1,3-thioxolan-4,2-diyl.
6. Compounds according to claim 1, wherein T is 2-,3- or 4-pyridyl.
7. Compounds according to claim 1, wherein T is carboxyl, (C1-C3)-alkoxycarbonyl carboxyamide, -CONRdRe, (3-pyridyl)methyl-aminocarbonyl, -CO-NH-CH(Rc)-CO2Ra, wherein Rc is residue of an .alpha.-aminoacid, selected from the group consisting of N-glycine, N-valine or N-histidine.
8. Compounds according to claim 1, wherein R1, R2 and R3 are hydrogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C2-C4)-alkenyl, halogen, (C1-C5)-acylamino, or imidazolyl.
9. Process for preparation of compounds I defined in claim 1, characterized by reacting a compound of general formula II
(II) with a compound of general formula III
(T)-(R)-W (III) wherein R, R1, R2, R3, B, Ar and T are as defined in claim 1 and one of Z and W is OH or SH, while the other is a leaving group.
(II) with a compound of general formula III
(T)-(R)-W (III) wherein R, R1, R2, R3, B, Ar and T are as defined in claim 1 and one of Z and W is OH or SH, while the other is a leaving group.
10. Pharmaceutical compositions containing a compound according to claim 1,2,3,4,5,6,7 or 8, and a pharmaceutically acceptable carrier or adjuvant material.
11. Use of compounds according to claim 1,2,3,4,5,6,7 or 8 for the preparation of pharmaceutical compositions with mucolytic or antitussive activities.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21657/87A IT1222500B (en) | 1987-08-14 | 1987-08-14 | THERAPEUTIC ETHERS AND TIOTERI, THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM |
| IT21657A/87 | 1987-08-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1326668C true CA1326668C (en) | 1994-02-01 |
Family
ID=11184932
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000574445A Expired - Fee Related CA1326668C (en) | 1987-08-14 | 1988-08-11 | Ethers and thioethers having therapeutical activity, their preparation and pharmaceutical compositions containing them |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US4968706A (en) |
| EP (1) | EP0303227B1 (en) |
| JP (1) | JPS6490149A (en) |
| AT (1) | ATE72433T1 (en) |
| CA (1) | CA1326668C (en) |
| DD (1) | DD277069A5 (en) |
| DE (1) | DE3868302D1 (en) |
| DK (1) | DK449788A (en) |
| ES (1) | ES2034062T3 (en) |
| FI (1) | FI883730A (en) |
| HU (1) | HU201749B (en) |
| IT (1) | IT1222500B (en) |
| NZ (1) | NZ225800A (en) |
| PT (1) | PT88242B (en) |
| ZA (1) | ZA885932B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5268007A (en) * | 1986-12-29 | 1993-12-07 | The Lubrizol Corporation | Dioxolanes and thio analogs, derivatives thereof and lubricants and fuels containing same |
| JP4653966B2 (en) * | 2004-04-19 | 2011-03-16 | ダイセル化学工業株式会社 | Method for producing 2-benzoyloxyacetaldehyde derivative |
| DE102012003286A1 (en) * | 2012-02-20 | 2013-08-22 | Merz Pharma Gmbh & Co. Kgaa | Combination of lipid transfer proteins and phenol derivatives containing plant substances with local mucosal efficiency |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4097581A (en) * | 1975-12-12 | 1978-06-27 | Ciba-Geigy Corporation | Dioxolane derivatives |
| GB8314521D0 (en) * | 1983-05-25 | 1983-06-29 | Pickett J A | Behaviour modifying compounds |
-
1987
- 1987-08-14 IT IT21657/87A patent/IT1222500B/en active
-
1988
- 1988-08-09 ES ES198888112922T patent/ES2034062T3/en not_active Expired - Lifetime
- 1988-08-09 EP EP88112922A patent/EP0303227B1/en not_active Expired - Lifetime
- 1988-08-09 AT AT88112922T patent/ATE72433T1/en not_active IP Right Cessation
- 1988-08-09 DE DE8888112922T patent/DE3868302D1/en not_active Expired - Lifetime
- 1988-08-11 PT PT88242A patent/PT88242B/en not_active IP Right Cessation
- 1988-08-11 ZA ZA885932A patent/ZA885932B/en unknown
- 1988-08-11 US US07/230,821 patent/US4968706A/en not_active Expired - Fee Related
- 1988-08-11 DK DK449788A patent/DK449788A/en not_active Application Discontinuation
- 1988-08-11 HU HU884315A patent/HU201749B/en not_active IP Right Cessation
- 1988-08-11 NZ NZ225800A patent/NZ225800A/en unknown
- 1988-08-11 FI FI883730A patent/FI883730A/en not_active Application Discontinuation
- 1988-08-11 CA CA000574445A patent/CA1326668C/en not_active Expired - Fee Related
- 1988-08-12 DD DD88318906A patent/DD277069A5/en not_active IP Right Cessation
- 1988-08-12 JP JP63201782A patent/JPS6490149A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE3868302D1 (en) | 1992-03-19 |
| DK449788A (en) | 1989-02-15 |
| ZA885932B (en) | 1989-04-26 |
| IT1222500B (en) | 1990-09-05 |
| ES2034062T3 (en) | 1993-04-01 |
| HU201749B (en) | 1990-12-28 |
| DK449788D0 (en) | 1988-08-11 |
| HUT49110A (en) | 1989-08-28 |
| EP0303227A1 (en) | 1989-02-15 |
| JPS6490149A (en) | 1989-04-06 |
| DD277069A5 (en) | 1990-03-21 |
| NZ225800A (en) | 1990-07-26 |
| PT88242A (en) | 1989-06-30 |
| IT8721657A0 (en) | 1987-08-14 |
| US4968706A (en) | 1990-11-06 |
| FI883730A0 (en) | 1988-08-11 |
| FI883730A (en) | 1989-02-15 |
| AU2067288A (en) | 1989-02-16 |
| EP0303227B1 (en) | 1992-02-05 |
| AU613656B2 (en) | 1991-08-08 |
| ATE72433T1 (en) | 1992-02-15 |
| PT88242B (en) | 1995-03-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4855464A (en) | Optically active ketals, processes for their preparation and their use in the synthesis of alpha-arylalkanoic acids | |
| EP0056172B1 (en) | Phenoxy- and thiophenoxy compounds, methods for their preparation and pharmaceutical formulations containing them | |
| US5202335A (en) | Succinic acid compounds | |
| EP0308573A2 (en) | Intermediates useful in the preparation of dopamine-beta-hydroxylase inhibitors | |
| HU214054B (en) | Novel process for preparing formoterol and it's n-alkyl-derivatives | |
| US5066801A (en) | Preparation of sulfonic acid esters | |
| CA1326668C (en) | Ethers and thioethers having therapeutical activity, their preparation and pharmaceutical compositions containing them | |
| WO1991005775A1 (en) | Aryl-3 oxazolidinones and their preparation and use | |
| MXPA02007295A (en) | Alkynylsubstituted propionic acid derivatives and their use against diabetes and obesity. | |
| EP1205476B1 (en) | Process for the synthesis of N-(mercaptoacyl)-amino acids derivatives from alpha-substituted acrylic acids | |
| US5212316A (en) | Ethers and thioethers having therapeutical activity, their preparation and pharmaceutical compositions containing them | |
| US4649160A (en) | Substituted phenoxy-aminopropanols | |
| CA2508623A1 (en) | Benzomorpholine derivatives | |
| CA2368623A1 (en) | 3-amidinobenzenesulfonamide derivatives, medicinal compositions containing the same and intermediates in the production thereof | |
| FI84347C (en) | Process for preparing 4-acetyl-2-substituted-imidazoles | |
| FR2586417A1 (en) | HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION | |
| US5468865A (en) | Stereopreferential synthesis of 3-(1-phenylprop-2-yl)-5-phenyloxazolidinones | |
| FI92688C (en) | Process for the preparation of optically active arylalkanecarboxylic acids | |
| FR2693723A1 (en) | Derivatives of N- (phenylethyl-beta-ol) amine and their process of preparation. | |
| FI93642C (en) | Process for Preparation of Optically Active -arylalkanecarboxylic Acids | |
| IE46590B1 (en) | Propanolamine derivatives | |
| HU221274B1 (en) | 3-[cyano-3-(3,4-dichlor-phenyl)]-propionic acid and process for preparation of one its isomer | |
| LU86775A1 (en) | HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION | |
| NO173055B (en) | PROCEDURE FOR THE PREPARATION OF ALFA-ARYLALIC ACIDS | |
| LU83186A1 (en) | NOVEL 1 - ((2-MERCAPTOCYCLOALKYL) CARBONYL) -L-PROLINES DERIVATIVES, PROCESS FOR THEIR MANUFACTURE, INTERMEDIATE PRODUCTS FOR THEIR SYNTHESIS AND THEIR USE AS ANTIHYPERTENSIVE AGENTS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |